Substituted 6-azabenzimidazole compounds

ABSTRACT

The present disclosure relates generally to certain 6-azabenzimidazole compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. The compounds and compositions disclosed herein may be used for the treatment or prevention of diseases, disorders, or infections modifiable by hematopoietic progenitor kinase 1 (HPK1) inhibitors, such as HBV, HIV, cancer, and/or a hyper-proliferative disease.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.62/753,355, filed Oct. 31, 2018, which is incorporated herein in itsentirety for all purposes.

FIELD

This disclosure relates generally to certain 6-azabenzimidazolecompounds, pharmaceutical compositions comprising said compounds, andmethods of making and using said compounds and pharmaceuticalcompositions.

BACKGROUND

Immuno-oncology is a burgeoning area of cancer research, highlighted byinhibitor antibodies against the immune checkpoint receptors CTLA4, PD-1and PD-L1. Targeted disruption of these checkpoint pathways releases theimmune cell from key regulatory pathways, allowing for a boost in theimmune response against cancer cells. Current therapies utilizing theseantibodies are highlighted by both significant and durable response tomany different cancers but also by low overall response rates (<25%).Understanding and improving these response rates is a formidable goal,and the combination of checkpoint blockade with other immune activatingagents or cell based therapies could provide an inroad to expand uponpatient responses.

Hematopoietic progenitor kinase 1 (HPK1), a STE20 ser/thr kinase fromthe germinal center family of kinases, regulates the function of diverseimmune populations including T cells, B cells, and dendritic cells (Huet al., Gens Dev, 1996; Alzabin et al., J Immunol 2009). In T cells,HPK1 serves as a negative regulator of T cell receptor (TCR) signaling(Liou et al., Immunity 2000; Sauer et al., JBC 2001) by phosphorylatingSLP76 on serine 376, which induces the association of SLP76 with 14-3-3proteins, and leads to the disassociation of the signaling complex (DiBartolo et al., JEM 2007). Further supporting the role of HPK1 as anegative regulator of TCR signaling, murine HPK1 deficient T cells orHPK1 kinase inactive mutant T cells have enhanced ERK 1/2 activation andeffector cytokine secretion upon TCR activation compared to theirwild-type counterparts (Shui et al., Nat Immunol 2007; Hernandez et al.,Cell Reports 2018). Accordingly, a small molecule inhibitor of HPK1could provide a novel way to enhance anti-tumor immunity and alsoprovide a way to increase the response to checkpoint receptor blockade.

SUMMARY

In one aspect, provided herein is a compound of Formula I,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the        other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein each        C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH and halogen, or    -   R¹ and R² together with the carbon to which they are attached        form a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic        heterocyclyl having 1 or 2 heteroatoms independently selected        from N, O, and S, wherein the C₃₋₇ monocyclic cycloalkyl and the        4-6 membered monocyclic heterocyclyl are each optionally        substituted with one R¹¹ and are each optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy, or R¹ and R² together form ═O;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) —S(O)₂C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) H,        -   ii) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃            alkoxy, wherein the C₁₋₃ alkyl is optionally substituted            with 1-3 groups independently selected from —OH, halogen,            and C₁₋₃ alkoxy,        -   iii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   v) —NH₂,        -   vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   viii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   ix) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —CN, —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,            -   f) 4-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 4-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and                C₁₋₃ alkoxy, and            -   g) —OC(O)C₁₋₆ alkyl optionally substituted with one —OH;    -   R³ and R¹³ are each H, or    -   R³ and R¹³ together form ═O;    -   L¹ is a cyclobutylene optionally substituted with 1-6 groups        independently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃        alkoxy;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and            -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃                alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) —CN,        -   ii) a halogen,        -   iii) —OH,        -   iv) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   vi) —COOH, or        -   vii) —C(O)N(R²²)₂, wherein each R²² is independently H or            C₁₋₆ alkyl;    -   X¹ is Nor CR¹⁷;    -   R⁴, R⁵, R⁶, R¹⁰, and R¹⁷ are each independently H, halogen, C₁₋₃        alkyl, or C₁₋₃ alkoxy;    -   R⁷ is        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   Z is —O—, —C(R⁸)₂—, or —NR⁸—;    -   each R⁸ is independently H or C₁₋₃ alkyl;    -   A is a pyridinyl, pyridonyl, quinolinyl, or isoquinolinyl, each        of which is optionally substituted with 1-4 R⁹;    -   each R⁹ is independently        -   i) halogen,        -   ii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iii) —NH₂,        -   iv) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   v) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same            or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vi) —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vii) —S(O)₂C₁₋₆ alkyl,        -   viii) —S(O)₂N(R²³)₂, wherein each R²³ is independently H or            C₁₋₆ alkyl,        -   ix) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —OH,            -   b) halogen,            -   c) C₁₋₃ alkoxy,            -   d) C₃₋₇ monocyclic cycloalkyl,            -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from oxo and C₁₋₃ alkyl, and            -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl,        -   x) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   xi) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xii) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xiii) —COOH,        -   xiv) —C(O)N(R¹⁹)₂, or        -   xv) —C₁₋₃ alkylC(O)N(R¹⁹)₂; and    -   each R¹⁹ is independently        -   i) H,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl,        -   iv) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein the C₁₋₆ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or v) 4-6            membered monocyclic heterocyclyl having 1-3 heteroatoms        -   independently selected from N, O, and S, wherein the 4-6            membered monocyclic heterocyclyl is optionally substituted            with 1-6 groups independently selected from —CN, —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient or carrier. Insome embodiments, the pharmaceutical compositions comprise atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In one aspect, the present disclosure provides methods of inhibitingHPK1 activity in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound providedherein (e.g, a compound of Formula I, II, IIa, III, IV, or V), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treating adisease or disorder associated with increased HPK1 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of increasingT-cell activation in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (e.g, a compound of Formula I, II, IIa, III, IV, or V), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treatingcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(e.g., a compound of Formula I, II, IIa, III, IV, or V), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of inhibiting thegrowth or proliferation of cancer cells in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula I, II,IIa, III, IV, or V), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition provided herein.

DETAILED DESCRIPTION I. Definitions

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. It must be noted that as used herein and in the appendedclaims, the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, e.g,reference to “the compound” includes a plurality of such compounds andreference to “the assay” includes reference to one or more assays andequivalents thereof known to those skilled in the art, and so forth.

As used in the present disclosure, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named. A solid line comingout of the center of a ring indicates that the point of attachment for asubstituent on the ring can be at any ring atom. For example, R^(a) inthe below structure can be attached to any of the five carbon ring atomsor R^(a) can replace the hydrogen attached to the nitrogen ring atom:

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings,wherein x and y are numerical ranges, such as “3 to 12-memberedheterocyclyl”, refers to a ring containing x-y atoms (e.g, 3-12), ofwhich up to 80% may be heteroatoms, such as N, O, S, P, and theremaining atoms are carbon.

Also, certain commonly used alternative chemical names may or may not beused. For example, a divalent group such as a divalent “alkyl” group, adivalent “aryl” group, etc., may also be referred to as an “alkylene”group or an “alkylenyl” group, or alkylyl group, an “arylene” group oran “arylenyl” group, or arylyl group, respectively.

“A compound disclosed herein” or “a compound of the present disclosure”or “a compound provided herein” or “a compound described herein” refersto the compounds of Formula I, II, IIa, III, IV, and/or V. Also includedare the specific compounds of Examples 1 to 195.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, the term “about X” includesdescription of “X”.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.,—(CH₂)₃CH₃), sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e.,—CH₂CH(CH₃)₂) and tert-butyl (i.e., —C(CH₃)₃); and “propyl” includesn-propyl (i.e., —(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl).Examples of alkenyl groups include ethenyl, propenyl, butadienyl(including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Haloalkoxy”refers to an alkoxy group as defined above, wherein one or more hydrogenatoms are replaced by a halogen.

“Acyl” refers to a group —C(═O)R, wherein R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein. Examples of acylinclude formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl,and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(═O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(═O)R^(z), wherein R^(y) and R^(z) are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, haloalkyl,heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionallysubstituted.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of whichmay be optionally substituted.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl ring, the resultingring system is heteroaryl.

“Cyano” or “carbonitrile” refers to the group —CN.

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e., the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Bridged” refers to a ring fusion wherein non-adjacent atoms on a ringare joined by a divalent substituent, such as an alkylenyl group, analkylenyl group containing one or two heteroatoms, or a singleheteroatom. Quinuclidinyl and admantanyl are examples of bridged ringsystems.

The term “fused” refers to a ring which is bound to an adjacent ring.

“Spiro” refers to a ring substituent which is joined by two bonds at thesame carbon atom. Examples of spiro groups include1,1-diethylcyclopentane, dimethyl-dioxolane, and4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine,respectively, are the spiro substituents.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 carbon ring atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 ringheteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen, and sulfur. Examples of heteroaryl groups includepyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Heterocyclyl” or “heterocyclic ring” or “heterocycle” refers to anon-aromatic cyclic alkyl group, with one or more ring heteroatomsindependently selected from nitrogen, oxygen and sulfur. As used herein,“heterocyclyl” or “heterocyclic ring” or “heterocycle” refer to ringsthat are saturated or partially saturated unless otherwise indicated,e.g., in some embodiments “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to rings that are partially saturated wherespecified. The term “heterocyclyl” or “heterocyclic ring” or“heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclylgroup having at least one double bond). A heterocyclyl may be a singlering or multiple rings wherein the multiple rings may be fused, bridged,or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms(i.e., C₂₋₂₀ heterocyclyl), 2 to 12 carbon ring atoms (i.e., C₂₋₁₂heterocyclyl), 2 to 10 carbon ring atoms (i.e., C₂₋₁₀ heterocyclyl), 2to 8 carbon ring atoms (i.e., C2-8 heterocyclyl), 3 to 12 carbon ringatoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 carbon ring atoms (i.e., C₃₋₈heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C₃₋₆ heterocyclyl);having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ringheteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independentlyselected from nitrogen, sulfur or oxygen. Examples of heterocyclylgroups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl,dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“bridged-heterocyclyl” refers to a four- to ten-membered cyclic moietyconnected at two non-adjacent atoms of the heterocyclyl with one or more(e.g., 1 or 2) four- to ten-membered cyclic moiety having at least oneheteroatom where each heteroatom is independently selected fromnitrogen, oxygen, and sulfur. As used herein, “bridged-heterocyclyl”includes bicyclic and tricyclic ring systems. Also as used herein, theterm “spiro-heterocyclyl” refers to a ring system in which a three- toten-membered heterocyclyl has one or more additional ring, wherein theone or more additional ring is three- to ten-membered cycloalkyl orthree- to ten-membered heterocyclyl, where a single atom of the one ormore additional ring is also an atom of the three- to ten-memberedheterocyclyl. Examples of the spiro-heterocyclyl include bicyclic andtricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl,2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. As usedherein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring”are used interchangeably. In some embodiments, a heterocyclyl issubstituted with an oxo group.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to the group (═O) or (O).

“Sulfonyl” refers to the group —S(O)₂R^(c), where R^(c) is alkyl,haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples ofsulfonyl are methyl sulfonyl, ethylsulfonyl, phenyl sulfonyl, andtoluenesulfonyl.

Whenever the graphical representation of a group terminates in a singlybonded nitrogen atom, that group represents an —NH group unlessotherwise indicated. Similarly, unless otherwise expressed, hydrogenatom(s) are implied and deemed present where necessary in view of theknowledge of one of skill in the art to complete valency or providestability.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” means that any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino,imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl,thiocyanate, thiol, thione, or combinations thereof. Polymers or similarindefinite structures arrived at by defining substituents with furthersubstituents appended ad infinitum (e.g, a substituted aryl having asubstituted alkyl which is itself substituted with a substituted arylgroup, which is further substituted by a substituted heteroalkyl group,etc.) are not intended for inclusion herein. Unless otherwise noted, themaximum number of serial substitutions in compounds described herein isthree. For example, serial substitutions of substituted aryl groups withtwo other substituted aryl groups are limited to ((substitutedaryl)substituted aryl) substituted aryl. Similarly, the abovedefinitions are not intended to include impermissible substitutionpatterns (e.g., methyl substituted with 5 fluorines or heteroaryl groupshaving two adjacent oxygen ring atoms). Such impermissible substitutionpatterns are well known to the skilled artisan. When used to modify achemical group, the term “substituted” may describe other chemicalgroups defined herein. For example, the term “substituted aryl”includes, but is not limited to, “alkylaryl.” Unless specifiedotherwise, where a group is described as optionally substituted, anysubstituents of the group are themselves unsubstituted.

In some embodiments, the term “substituted alkyl” refers to an alkylgroup having one or more substituents including hydroxyl, halo, amino,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additionalembodiments, “substituted cycloalkyl” refers to a cycloalkyl grouphaving one or more substituents including alkyl, haloalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one ormore substituents including alkyl, amino, haloalkyl, heterocyclyl,cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or moresubstituents including halo, alkyl, amino, haloalkyl, cycloalkyl,heterocyclyl, heteroaryl, alkoxy, and cyano; “substituted heteroaryl”refers to an heteroaryl group having one or more substituents includinghalo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to agroup —S(O)₂R, in which R is substituted with one or more substituentsincluding alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Inother embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is unsubstituted.

In some embodiments, a substituted cycloalkyl, a substitutedheterocyclyl, a substituted aryl, and/or a substituted heteroarylincludes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl thathas a substituent on the ring atom to which the cycloalkyl,heterocyclyl, aryl, and/or heteroaryl is attached to the rest of thecompound. For example, in the below moiety, the cyclopropyl issubstituted with a methyl group:

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Wherecompounds are represented in their chiral form, it is understood thatthe embodiment encompasses, but is not limited to, the specificdiastereomerically or enantiomerically enriched form. Where chirality isnot specified but is present, it is understood that the embodiment isdirected to either the specific diastereomerically or enantiomericallyenriched form; or a racemic or scalemic mixture of such compound(s). Asused herein, “scalemic mixture” is a mixture of stereoisomers at a ratioother than 1:1.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any compounds provided herein.

Some of the compounds provided herein exist as tautomeric isomers.Tautomeric isomers are in equilibrium with one another. For example,amide containing compounds may exist in equilibrium with imidic acidtautomers. Regardless of which tautomer is shown, and regardless of thenature of the equilibrium among tautomers, the compounds are understoodby one of ordinary skill in the art to comprise both amide and imidicacid tautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds provided herein are also provided.Hydrates of the compounds provided herein are also provided.

Any formula or structure provided herein is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ²H, ³H, ¹³C and ¹⁴C are incorporated,are also provided herein. Such isotopically labelled compounds may beuseful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The present disclosure also includes compounds of Formula I, II, IIa,III, IV, or V, in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I, II, IIa, III, IV, or V, when administered to a mammal,particularly a human. See, for example, Foster, “Deuterium IsotopeEffects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well knownin the art, for example by employing starting materials in which one ormore hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of the presentdisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to absorption, distribution, metabolism andexcretion (ADME). Substitution with heavier isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life, reduceddosage requirements and/or an improvement in therapeutic index. An ¹⁸Flabeled compound may be useful for PET or SPECT studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in the compound of Formula I, II, IIa, III,IV, or V.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure, any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosure,any atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono,di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines,and the like. Specific examples of suitable amines include, by way ofexample only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,2-dimethylaminoethanol, piperazine, piperidine, morpholine,N-ethylpiperidine, and the like.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g, ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival).

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof means an amount sufficient to effect treatment whenadministered to a subject, to provide a therapeutic benefit such asamelioration of symptoms or slowing of disease progression. For example,a therapeutically effective amount may be an amount sufficient todecrease a symptom of a disease or condition responsive to inhibition ofhematopoietic progenitor kinase 1 (HPK1) activity. The therapeuticallyeffective amount may vary depending on the subject, and the disease orcondition being treated, the weight and age of the subject, the severityof the disease or condition, and the manner of administering, which canreadily be determined by one of ordinary skill in the art.

The term “inhibition” indicates a decrease in the baseline activity of abiological activity or process. “Inhibition of activity of HPK1” orvariants thereof refers to a decrease in HPK1 activity as a direct orindirect response to the presence of a compound of the presentdisclosure relative to the HPK1 activity in the absence of the compoundof the present disclosure. “Inhibition of HPK1” refers to a decrease inHPK1 activity as a direct or indirect response to the presence of acompound provided herein relative to the HPK1 activity in the absence ofthe compound provided herein. In some embodiments, the inhibition ofHPK1 activity may be compared in the same subject prior to treatment, orother subjects not receiving the treatment.

II. Compounds

In one aspect, provided herein is a compound of Formula I,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the        other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein each        C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH and halogen, or    -   R¹ and R² together with the carbon to which they are attached        form a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic        heterocyclyl having 1 or 2 heteroatoms independently selected        from N, O, and S, wherein the C₃₋₇ monocyclic cycloalkyl and the        4-6 membered monocyclic heterocyclyl are each optionally        substituted with one R¹¹ and are each optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy, or    -   R¹ and R² together form ═O;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) —S(O)₂C₃₋₇ monocyclic cycloalkyl,        -   iv) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or        -   v) —C(O)R²¹;    -   R²¹ is        -   i) H,        -   ii) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃            alkoxy, wherein the C₁₋₃ alkyl is optionally substituted            with 1-3 groups independently selected from —OH, halogen,            and C₁₋₃ alkoxy,        -   iii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   v) —NH₂,        -   vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy,        -   viii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl, or        -   ix) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —CN, —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,            -   f) 4-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 4-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and                C₁₋₃ alkoxy, and            -   g) —OC(O)C₁₋₆ alkyl optionally substituted with one —OH;    -   R³ and R¹³ are each H, or    -   R³ and R¹³ together form ═O;    -   L¹ is a cyclobutylene optionally substituted with 1-6 groups        independently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃        alkoxy;    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H,        -   ii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   iii) 4-7 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-7 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy, or        -   v) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted                with 1-3 groups independently selected from —OH,                halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and            -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃                alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) —CN,        -   ii) a halogen,        -   iii) —OH,        -   iv) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl,        -   vi) —COOH, or        -   vii) —C(O)N(R²²)₂, wherein each R²² is independently H or            C₁₋₆ alkyl;    -   X¹ is Nor CR¹⁷;    -   R⁴, R⁵, R⁶, R¹⁰, and R¹⁷ are each independently H, halogen, C₁₋₃        alkyl, or C₁₋₃ alkoxy;    -   R⁷ is        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   iii) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy;    -   Z is —O—, —C(R⁸)₂—, or —NR⁸—;    -   each R⁸ is independently H or C₁₋₃ alkyl;    -   A is a pyridinyl, pyridonyl, quinolinyl, or isoquinolinyl, each        of which is optionally substituted with 1-4 R⁹;    -   each R⁹ is independently        -   i) halogen,        -   ii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iii) —NH₂,        -   iv) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   v) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same            or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vi) —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the            same or different, and wherein each C₁₋₆ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vii) —S(O)₂C₁₋₆ alkyl,        -   viii) —S(O)₂N(R²³)₂, wherein each R²³ is independently H or            C₁₋₆ alkyl,        -   ix) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —OH,            -   b) halogen,            -   c) C₁₋₃ alkoxy,            -   d) C₃₋₇ monocyclic cycloalkyl,            -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 5-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from oxo and C₁₋₃ alkyl, and            -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl,        -   x) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-3 groups independently selected from —OH, halogen, C₁₋₃            alkyl, and C₁₋₃ alkoxy,        -   xi) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xii) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   xiii) —COOH,        -   xiv) —C(O)N(R¹⁹)₂, or        -   xv) —C₁₋₃ alkylC(O)N(R¹⁹)₂; and    -   each R¹⁹ is independently        -   i) H,        -   ii) —S(O)₂C₁₋₆ alkyl,        -   iii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl,        -   iv) C₃₋₇ monocyclic cycloalkyl optionally substituted with            1-6 groups independently selected from —CN, —OH, halogen,            C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein the C₁₋₆ alkyl is            optionally substituted with 1-3 groups independently            selected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or        -   v) 4-6 membered monocyclic heterocyclyl having 1-3            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-6 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments, the compound of Formula I is of Formula II,

or a pharmaceutically acceptable salt thereof,wherein

-   -   each R¹² is independently —OH, halogen, C₁₋₃ alkyl, or C₁₋₃        alkoxy; and    -   n is 0, 1, 2, 3, or 4;    -   and the remaining variables are as defined as in Formula I.

In some embodiments, the compound of Formula I or II is of Formula IIa,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments of the compound of Formula I, II or IIa, or apharmaceutically acceptable salt thereof, R³ and R¹³ together form ═O.In some embodiments of the compound of Formula I, II or IIa, or apharmaceutically acceptable salt thereof, R³ and R¹³ are each H.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, X¹ is CR¹⁷.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R¹⁷ is H. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, R¹⁷ is halogen. In some embodiments of thecompound of Formula I, II, or IIa, or a pharmaceutically acceptable saltthereof, R¹⁷ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, or IIa, or a pharmaceutically acceptable salt thereof,R¹⁷ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, X¹ is CH. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, X¹ is N.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, Z is —NR⁸—. In someembodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, Z is —C(R⁸)₂—.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁸ is H. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, R⁸ is C₁₋₃ alkyl.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, Z is —NH—. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, Z is —CH₂—. In some embodiments of the compoundof Formula I, II, or IIa, or a pharmaceutically acceptable salt thereof,Z is —O—.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁴ is H. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, R⁴ is halogen. In some embodiments of thecompound of Formula I, II, or IIa, or a pharmaceutically acceptable saltthereof, R⁴ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, or IIa, or a pharmaceutically acceptable salt thereof, R⁴is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁵ is H. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, R⁵ is halogen. In some embodiments of thecompound of Formula I, II, or IIa, or a pharmaceutically acceptable saltthereof, R⁵ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, or IIa, or a pharmaceutically acceptable salt thereof, R⁵is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁶ is H. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, R⁶ is halogen. In some embodiments of thecompound of Formula I, II, or IIa, or a pharmaceutically acceptable saltthereof, R⁶ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, or IIa, or a pharmaceutically acceptable salt thereof, R⁶is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R¹⁰ is H. In some embodimentsof the compound of Formula I, II, or IIa, or a pharmaceuticallyacceptable salt thereof, R¹⁰ is halogen. In some embodiments of thecompound of Formula I, II, or IIa, or a pharmaceutically acceptable saltthereof, R¹⁰ is C₁₋₃ alkyl. In some embodiments of the compound ofFormula I, II, or IIa, or a pharmaceutically acceptable salt thereof,R¹⁰ is C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶, and R¹⁰ are H. Insome embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶, R¹⁰, and R¹⁷ areH. In some embodiments of the compound of Formula I, II, or IIa, or apharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶, and R¹⁰ are H; X¹is CH; and Z is NFL In some embodiments of the compound of Formula I,II, or IIa, or a pharmaceutically acceptable salt thereof, R⁴, R⁵, R⁶,and R¹⁰ are H; X¹ is N; and Z is NFL

In some embodiments of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, L¹ is a cyclobutylene optionally substitutedwith 1, 2, 3, 4, 5, or 6 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, or a pharmaceutically acceptable salt thereof, L¹is a cyclobutylene. In some embodiments of the compound of Formula I, ora pharmaceutically acceptable salt thereof, L¹ is a cyclobutylenesubstituted with one C₁₋₃ alkyl group. In some embodiments of thecompound of Formula I, or a pharmaceutically acceptable salt thereof, L¹is a cyclobutylene substituted with one methyl group.

In some embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, R¹² is OH. In some embodimentsof the compound of Formula II or IIa, or a pharmaceutically acceptablesalt thereof, R¹² is halogen. In some embodiments of the compound ofFormula II or IIa, or a pharmaceutically acceptable salt thereof, R¹² isC₁₋₃ alkyl. In some embodiments of the compound of Formula II or IIa, ora pharmaceutically acceptable salt thereof, R¹² is C₁₋₃ alkoxy. In someembodiments of the compound of Formula II or IIa, or a pharmaceuticallyacceptable salt thereof, R¹² is methyl.

In some embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, n is 0, 1, 2, 3, or 4. In someembodiments of the compound of Formula II or IIa, or a pharmaceuticallyacceptable salt thereof, n is 0, 1, 2, or 3. In some embodiments of thecompound of Formula II or IIa, or a pharmaceutically acceptable saltthereof, n is 0, 1, or 2. In some embodiments of the compound of FormulaII or IIa, or a pharmaceutically acceptable salt thereof, n is 0 or 1.In some embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, n is 0. In some embodiments ofthe compound of Formula II or IIa, or a pharmaceutically acceptable saltthereof, n is 1. In some embodiments of the compound of Formula II orIIa, or a pharmaceutically acceptable salt thereof, n is 2. In someembodiments of the compound of Formula II or IIa, or a pharmaceuticallyacceptable salt thereof, n is 3. In some embodiments of the compound ofFormula II or IIa, or a pharmaceutically acceptable salt thereof, n is4.

In some embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, nisi and R¹² is C₁₋₃ alkyl. Insome embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, n is 1 and R¹² is methyl. Insome embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, nisi and R¹² is C₁₋₃ alkyl. Insome embodiments of the compound of Formula II or IIa, or apharmaceutically acceptable salt thereof, n is 1 and R¹² is methyl.

In some embodiments, the compound of Formula I, II, or IIa is of FormulaIII,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined as in Formula I.

In some embodiments, the compound of Formula I, II, or IIa is of FormulaIII,

or a pharmaceutically acceptable salt thereof,wherein:

-   -   one of R¹ and R² is —OH or C₁₋₃ alkyl, and the other of R¹ and        R² is C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy;    -   R¹¹ is        -   i) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, or        -   ii) —C(O)R²¹;    -   R²¹ is        -   i) C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃            alkyl is optionally substituted with 1-3 groups            independently selected from —OH, halogen, and C₁₋₃ alkoxy,        -   ii) 4-6 membered monocyclic heterocyclyl having 1 or 2            heteroatoms independently selected from N, O, and S, wherein            the 4-6 membered monocyclic heterocyclyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy,        -   iii) 5-6 membered monocyclic heteroaryl having 1-4            heteroatoms independently selected from N, O, and S, wherein            the 5-6 membered monocyclic heteroaryl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, or        -   iv) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   v) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from            -   a) —CN,            -   b) —OH,            -   c) halogen,            -   d) C₁₋₃ alkoxy,            -   e) 4-6 membered monocyclic heterocyclyl having 1 or 2                heteroatoms independently selected from N, O, and S,                wherein the 4-6 membered monocyclic heterocyclyl is                optionally substituted with 1-3 groups independently                selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and                C₁₋₃ alkoxy, and    -   X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently        -   i) H, or        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from            -   a) —OH,            -   b) halogen, and            -   c) C₁₋₃ alkoxy; or    -   X is a 4-10 membered monocyclic, fused bicyclic, bridged        bicyclic, or spirocyclic heterocyclyl having 1-3 heteroatoms        independently selected from N, O, and S, wherein the 4-10        membered monocyclic, fused bicyclic, bridged bicyclic, or        spirocyclic heterocyclyl is optionally substituted with 1-5 R¹⁸;    -   each R¹⁸ is independently        -   i) a halogen,        -   ii) —OH, or        -   iii) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl;    -   R⁷ is C₁₋₆ alkyl optionally substituted with 1-3 groups        independently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇        monocyclic cycloalkyl;    -   A is a pyridinyl, pyridonyl, or isoquinolinyl, each of which is        optionally substituted with 1-4 R⁹;    -   each R⁹ is independently        -   i) a halogen,        -   ii) C₁₋₆ alkoxy optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkyl, and            C₃₋₇ monocyclic cycloalkyl,        -   iii) —NH₂,        -   iv) —NH(C₁₋₃ alkyl), wherein the C₁₋₃ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   v) —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkyl can be the same            or different, and wherein each C₁₋₃ alkyl is optionally            substituted with 1-3 groups independently selected from —OH,            halogen, and C₁₋₃ alkoxy,        -   vi) C₁₋₆ alkyl optionally substituted with 1-3 groups            independently selected from —OH, halogen, C₁₋₃ alkoxy, and            C₃₋₇ monocyclic cycloalkyl, or        -   vii) —C(O)N(R¹⁹)₂; and    -   each R¹⁹ is independently        -   i) H,        -   ii) C₁₋₆ alkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy,            and C₃₋₇ monocyclic cycloalkyl, or iii) C₃₋₇ monocyclic            cycloalkyl optionally substituted with 1-6 groups            independently selected from —CN, —OH, halogen, C₁₋₃ alkyl,            and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is optionally            substituted with 1-3 groups independently selected from —CN,            —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof,

-   -   one of R¹ and R² is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the        other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein each        C₁₋₆ alkyl is optionally substituted with 1-3 groups        independently selected from —OH and halogen, or    -   R¹ and R² together with the carbon to which they are attached        form a C₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic        heterocyclyl having 1 or 2 heteroatoms independently selected        from N, O, and S, wherein the C₃₋₇ monocyclic cycloalkyl and the        4-6 membered monocyclic heterocyclyl are each optionally        substituted with one R¹¹ and are each optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy, or    -   R¹ and R² together form ═O.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof,

-   -   one of R¹ and R² is —OH or C₁₋₃ alkyl, and the other of R¹ and        R² is C₁₋₃ alkyl, or    -   R¹ and R² together with the carbon to which they are attached        form a 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with one R¹¹ and optionally substituted with 1-3 groups        independently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and        C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, R¹ and R² together form ═O.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is H, —CN,—OH, halogen, or C₁₋₆ alkyl, and the other of R¹ and R² is H, halogen,or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1-3groups independently selected from —OH and halogen. In some embodimentsof the compound of Formula I, II, IIa, or III, or a pharmaceuticallyacceptable salt thereof, one of R¹ and R² is H and the other of R¹ andR² is H, halogen, or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH and halogen.In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is —CN andthe other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH and halogen. In some embodiments of the compound of Formula I,II, IIa, or III, or a pharmaceutically acceptable salt thereof, one ofR¹ and R² is —OH and the other of R¹ and R² is H, halogen, or C₁₋₆alkyl, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH and halogen. In some embodiments of thecompound of Formula I, II, IIa, or III, or a pharmaceutically acceptablesalt thereof, one of R¹ and R² is halogen and the other of R¹ and R² isH, halogen, or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH and halogen.In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is C₁₋₆ alkyland the other of R¹ and R² is H, halogen, or C₁₋₆ alkyl, wherein eachC₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH and halogen. In some embodiments of the compound ofFormula I, II, IIa, or III, or a pharmaceutically acceptable saltthereof, one of R¹ and R² is C₁₋₃ alkyl and the other of R¹ and R² is H,halogen, or C₁₋₆ alkyl, wherein the C₁₋₃ alkyl and the C₁₋₆ alkyl areeach optionally substituted with 1-3 groups independently selected from—OH and halogen. In some embodiments of the compound of Formula I, II,IIa, or III, or a pharmaceutically acceptable salt thereof, one of R¹and R² is C₁₋₃ alkyl and the other of R¹ and R² is H, halogen, or C₁₋₆alkyl, wherein the C₁₋₃ alkyl is substituted with 1-3 OH groups. In someembodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is methyl,ethyl, or propyl and the other of R¹ and R² is H, halogen, or C₁₋₆alkyl, wherein the methyl, ethyl, or propyl are each substituted withone OH group.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is —OH orC₁₋₃ alkyl, and the other of R¹ and R² is C₁₋₃ alkyl. In someembodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is —OH andthe other of R¹ and R² is C₁₋₃ alkyl. In some embodiments of thecompound of Formula I, II, IIa, or III, or a pharmaceutically acceptablesalt thereof, R¹ and R² are each C₁₋₃ alkyl.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is —OH,methyl, or ethyl and the other of R¹ and R² is methyl or ethyl. In someembodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is —OH andthe other of R¹ and R² is methyl or ethyl. In some embodiments of thecompound of Formula I, II, IIa, or III, or a pharmaceutically acceptablesalt thereof, one of R¹ and R² is methyl and the other of R¹ and R² ismethyl or ethyl. In some embodiments of the compound of Formula I, II,IIa, or III, or a pharmaceutically acceptable salt thereof, one of R¹and R² is ethyl and the other of R¹ and R² is methyl or ethyl.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, one of R¹ and R² is methyl or—OH and the other of R¹ and R² is methyl. In some embodiments of thecompound of Formula I, II, IIa, or III, or a pharmaceutically acceptablesalt thereof, both R¹ and R² are methyl. In some embodiments of thecompound of Formula I, II, IIa, or III, or a pharmaceutically acceptablesalt thereof, one of R¹ and R² is —OH and the other of R¹ and R² ismethyl.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a C₃₋₇ monocyclic cycloalkyl or a4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatomsindependently selected from N, O, and S, wherein the C₃₋₇ monocycliccycloalkyl and the 4-6 membered monocyclic heterocyclyl are eachoptionally substituted with one R¹¹ and are each optionally substitutedwith 1-3 groups independently selected from —OH, halogen, oxo, C₁₋₃alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound of FormulaI, II, IIa, or III, or a pharmaceutically acceptable salt thereof, R¹and R² together with the carbon to which they are attached form a C₃₋₇monocyclic cycloalkyl optionally substituted with one R¹¹ and optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, or III, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a C₃₋₇ monocyclic cycloalkyl substituted with one R¹¹.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a 4-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with one R¹¹ and optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy. In some embodiments of the compound of Formula I, II, IIa, orIII, or a pharmaceutically acceptable salt thereof, R¹ and R² togetherwith the carbon to which they are attached form a 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl issubstituted with one R¹¹.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a piperidinyl optionallysubstituted with one R¹¹ and optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy. In some embodiments of the compound of Formula I, II, IIa, orIII, or a pharmaceutically acceptable salt thereof, R¹ and R² togetherwith the carbon to which they are attached form a piperidinylsubstituted with one R¹¹.

In some embodiments, the compound of Formula I, II, IIa, or III is ofFormula IV,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments of the compound of Formula I, II, IIa, or III, or apharmaceutically acceptable salt thereof, R¹ and R² together with thecarbon to which they are attached form a tetrahydropyranyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, or III, or a pharmaceutically acceptable saltthereof, R¹ and R² together with the carbon to which they are attachedform a tetrahydropyranyl.

In some embodiments, the compound of Formula I, II, IIa, or III is ofFormula V,

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; ii) —S(O)₂C₁₋₆ alkyl;iii) —S(O)₂C₃₋₇ monocyclic cycloalkyl; iv) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; or v) —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is i) 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; or ii) —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₁₋₆ alkyl.In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂CH₃. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R¹¹ is —S(O)₂C₃₋₇ monocycliccycloalkyl. In some embodiments of the compound of Formula I, II, IIa,III, or IV, or a pharmaceutically acceptable salt thereof, R¹¹ is—S(O)₂(cyclopropyl). In some embodiments of the compound of Formula I,II, IIa, III, or IV, or a pharmaceutically acceptable salt thereof, R¹¹is C₁₋₆ alkyl optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocycliccycloalkyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is a 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments ofthe compound of Formula I, II, IIa, III, or IV, or a pharmaceuticallyacceptable salt thereof, R¹¹ is a 4 membered monocyclic heterocyclylhaving 1 or 2 heteroatoms independently selected from N, O, and S,wherein the 4 membered monocyclic heterocyclyl is optionally substitutedwith 1-3 groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound of FormulaI, II, IIa, III, or IV, or a pharmaceutically acceptable salt thereof,R¹¹ is oxetanyl optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R¹¹ is oxetanyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is —C(O)R²¹.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is i) H; ii) C₃₋₇monocyclic or bridged bicyclic cycloalkyl optionally substituted with1-3 groups independently selected from —CN, —OH, halogen, C₁₋₃ alkyl,and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy;iii) 4-6 membered monocyclic heterocyclyl having 1 or 2 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy; iv) 5-6 membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from N, O, and S, wherein the 5-6 memberedmonocyclic heteroaryl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy; v) —NH₂; vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy; vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆alkyl can be the same or different and wherein each C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy; viii) C₁₋₆ alkoxy optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl,and C₃₋₇ monocyclic cycloalkyl; or ix) C₁₋₆ alkyl optionally substitutedwith 1-3 groups independently selected from

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy,    -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —CN, —OH, halogen, C₁₋₃        alkyl, and C₁₋₃ alkoxy,    -   f) 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —CN, —OH, halogen,        oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and    -   g) —OC(O)C₁₋₆ alkyl optionally substituted with one —OH.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is i) C₃₋₇ monocyclicor bridged bicyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy; ii) 4-6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iii)5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independentlyselected from N, O, and S, wherein the 5-6 membered monocyclicheteroaryl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iv) C₁₋₆alkoxy optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl; or v)C₁₋₆ alkyl optionally substituted with 1-3 groups independently selectedfrom

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy, and    -   e) 4-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        4-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —CN, —OH, halogen,        oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is H. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is —NH₂. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is —NH(C₁₋₆ alkyl),wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is —N(C₁₋₆ alkyl)₂,wherein each C₁₋₆ alkyl can be the same or different and wherein eachC₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is C₃₋₇ monocyclic orbridged bicyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is cyclopropyl,cyclobutyl, cyclopentyl, or C₅ bridged bicyclic cycloalkyl, each ofwhich is optionally substituted with 1-3 groups independently selectedfrom —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH and halogen. In some embodiments of the compound of Formula I,II, IIa, III, or IV, or a pharmaceutically acceptable salt thereof, R²¹is cyclopropyl, cyclobutyl, cyclopentyl, or C₅ bridged bicycliccycloalkyl, each of which is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, methyl, and —OCH₃. Insome embodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is cyclopropyl optionallysubstituted with one group selected from —CN, —OH, fluoro, methyl,—CH₂OH, and —OCH₃. In some embodiments of the compound of Formula I, II,IIa, III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ iscyclobutyl optionally substituted with one group selected from fluoro,methyl, and —OCH₃. In some embodiments of the compound of Formula I, II,IIa, III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ iscyclopentyl optionally substituted with one —OH. In some embodiments ofthe compound of Formula I, II, IIa, III, or IV, or a pharmaceuticallyacceptable salt thereof, R²¹ is C₅ bridged bicyclic cycloalkyloptionally substituted with one group selected from —OH and fluoro. Asused herein, a C₅ bridged bicyclic cycloalkyl includes but is notlimited to:

which is the same as

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is a 4-6 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments ofthe compound of Formula I, II, IIa, III, or IV, or a pharmaceuticallyacceptable salt thereof, R²¹ is oxetanyl, tetrahydrofuranyl, ortetrahydropyranyl, each of which is optionally substituted with 1-3groups independently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy. In some embodiments of the compound of Formula I, II, IIa, III,or IV, or a pharmaceutically acceptable salt thereof, R²¹ is oxetanyloptionally substituted with one group selected from methyl, ethyl, andisopropyl. In some embodiments of the compound of Formula I, II, IIa,III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ istetrahydrofuranyl optionally substituted with one methyl. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is tetrahydropyranyloptionally substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is a 5-6 memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromN, O, and S, wherein the 5-6 membered monocyclic heteroaryl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, III, or IV, or a pharmaceuticallyacceptable salt thereof, R²¹ is a 5-membered heteroaryl having 1-4heteroatoms independently selected from N, O, and S, wherein the5-membered heteroaryl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, methyl, and —OCH₃. In someembodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is oxazolyl, thiazolyl,isoxazolyl, oxadiazolyl, or triazolyl, each of which is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, III, or IV, or a pharmaceutically acceptable saltthereof, R²¹ is oxazolyl. In some embodiments of the compound of FormulaI, II, IIa, III, or IV, or a pharmaceutically acceptable salt thereof,R²¹ is thiazolyl. In some embodiments of the compound of Formula I, II,IIa, III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ isisoxazolyl. In some embodiments of the compound of Formula I, II, IIa,III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ isoxadiazolyl. In some embodiments of the compound of Formula I, II, IIa,III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ istriazolyl optionally substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is a C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl. In some embodimentsof the compound of Formula I, II, IIa, III, or IV, or a pharmaceuticallyacceptable salt thereof, R²¹ is a C₁₋₃ alkoxy optionally substitutedwith 1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl,and C₃₋₇ monocyclic cycloalkyl. In some embodiments of the compound ofFormula I, II, IIa, III, or IV, or a pharmaceutically acceptable saltthereof, R²¹ is a C₁₋₃ alkoxy. In some embodiments of the compound ofFormula I, II, IIa, III, or IV, or a pharmaceutically acceptable saltthereof, R²¹ is —OCH₃.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from: —CN;—OH; halogen; C₁₋₃ alkoxy; C₃₋₇ monocyclic cycloalkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; 4-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; and —OC(O)C₁₋₆ alkyloptionally substituted with one —OH. In some embodiments of the compoundof Formula I, II, IIa, III, or IV, or a pharmaceutically acceptable saltthereof, R²¹ is C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —CN; —OH; halogen; C₁₋₃ alkoxy; and 4-6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. Insome embodiments of the compound of Formula I, II, IIa, III, or IV, or apharmaceutically acceptable salt thereof, R²¹ is C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, oxetanyl, and C₁₋₃ alkoxy. In some embodiments of the compoundof Formula I, II, IIa, III, or IV, or a pharmaceutically acceptable saltthereof, R²¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,or tert-butyl, each of which is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, oxetanyl, and C₁₋₃alkoxy. In some embodiments of the compound of Formula I, II, IIa, III,or IV, or a pharmaceutically acceptable salt thereof, R²¹ is methyloptionally substituted with one group selected from —CN, —OH, andoxetanyl. In some embodiments of the compound of Formula I, II, IIa,III, or IV, or a pharmaceutically acceptable salt thereof, R²¹ is ethyloptionally substituted with one group selected from —OH, fluoro, and—OCH₃. In some embodiments of the compound of Formula I, II, IIa, III,or IV, or a pharmaceutically acceptable salt thereof, R²¹ is n-propyloptionally substituted with one —OH. In some embodiments of the compoundof Formula I, II, IIa, III, or IV, or a pharmaceutically acceptable saltthereof, R²¹ is isopropyl optionally substituted with one group selectedfrom —CN, —OH and —OCH₃. In some embodiments of the compound of FormulaI, II, IIa, III, or IV, or a pharmaceutically acceptable salt thereof,R²¹ is isobutyl optionally substituted with one —OH. In some embodimentsof the compound of Formula I, II, IIa, III, or IV, or a pharmaceuticallyacceptable salt thereof, R²¹ is tert-butyl optionally substituted withone group selected from —OH, fluoro, and —OCH₃.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is methyl optionallysubstituted with one group selected from —CN, —OH, and oxetanyl; ethyloptionally substituted with one group selected from —OH, fluoro, and—OCH₃; n-propyl optionally substituted with one —OH; isopropyloptionally substituted with one group selected from —CN, —OH and —OCH₃;isobutyl optionally substituted with one —OH; tert-butyl optionallysubstituted with one group selected from —OH, fluoro, and —OCH₃; —OCH₃;cyclopropyl optionally substituted with one group selected from —CN,—OH, fluoro, methyl, —CH₂OH, and —OCH₃; cyclobutyl optionallysubstituted with one group selected from fluoro, methyl, and —OCH₃;cyclopentyl optionally substituted with one —OH; C₅ bridged bicycliccycloalkyl optionally substituted with one group selected from —OH andfluoro; oxetanyl optionally substituted with one group selected frommethyl, ethyl, and isopropyl; tetrahydrofuranyl optionally substitutedwith one methyl; tetrahydropyranyl optionally substituted with onemethyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyloptionally substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is methyl; methylsubstituted with one oxetanyl; —CH₂OH; —CH₂(CN); ethyl; —CH(CH₃)OH;—CH(CH₃)CH₂OH; —CH(CH₃)OCH₃; —CH(OH)CH₂CH₃; isopropyl; —C(CH₃)₂OH;—C(CH₃)₂OCH₃; —C(CH₃)₂CN; tert-butyl; —C(CH₃)₂CH₂OH; —C(CH₃)₂CH₂OCH₃;—C(CH₃)₂CH₂F; —CH(OH)CH(CH₃)₂; —OCH₃; cyclopropyl; cyclopropylsubstituted with one methyl; cyclopropyl substituted with one fluoro;cyclopropyl substituted with one —OCH₃; cyclopropyl substituted with one—OH; cyclopropyl substituted with one —CH₂OH; cyclopropyl substitutedwith one —CN; cyclobutyl; cyclobutyl substituted with one —OCH₃;cyclobutyl substituted with one methyl; cyclobutyl substituted with onefluoro; cyclopentyl substituted with one —OH; C₅ bridged bicycliccycloalkyl; C₅ bridged bicyclic cycloalkyl substituted with one fluoro;C₅ bridged bicyclic cycloalkyl substituted with one —OH; oxetanyl;oxetanyl substituted with one methyl; oxetanyl substituted with oneethyl; oxetanyl substituted with one isopropyl; tetrahydrofuranyl;tetrahydrofuranyl substituted with one methyl; tetrahydropyranyl;tetrahydropyranyl substituted with one methyl; oxazolyl; thiazolyl;isoxazolyl; oxadiazolyl; or triazolyl substituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is methyl; methylsubstituted with one oxetanyl; ethyl; —CH(CH₃)OH; —CH(CH₃)OCH₃;—CH(OH)CH₂CH₃; isopropyl; —C(CH₃)₂OH; —C(CH₃)₂OCH₃; —C(CH₃)₂CN;tert-butyl; —C(CH₃)₂CH₂OH; —C(CH₃)₂CH₂OCH₃; —C(CH₃)₂CH₂F;—CH(OH)CH(CH₃)₂; —OCH₃; cyclopropyl; cyclopropyl substituted with onemethyl; cyclopropyl substituted with one fluoro; cyclopropyl substitutedwith one —OCH₃; cyclopropyl substituted with one —CN; cyclobutylsubstituted with one —OCH₃; cyclobutyl substituted with one fluoro;cyclopentyl substituted with one —OH; C₅ bridged bicyclic cycloalkylsubstituted with one fluoro; oxetanyl; oxetanyl substituted with onemethyl; oxetanyl substituted with one ethyl; oxetanyl substituted withone isopropyl; tetrahydrofuranyl; tetrahydrofuranyl substituted with onemethyl; tetrahydropyranyl; tetrahydropyranyl substituted with onemethyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolylsubstituted with one methyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R²¹ is methyl.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,or a pharmaceutically acceptable salt thereof, R¹¹ is:

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is pyridinyl,pyridonyl, quinolinyl, or isoquinolinyl, each of which is optionallysubstituted with 1-4 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is pyridinyl,pyridonyl, or isoquinolinyl, each of which is optionally substitutedwith 1-4 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is pyridinyloptionally substituted with 1-4 R⁹. In some embodiments of the compoundof Formula I, II, IIa, III, IV, or V, or a pharmaceutically acceptablesalt thereof, A is pyridonyl optionally substituted with 1-4 R⁹. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, A is pyridonyl optionallysubstituted with 1-3 R⁹. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, A is quinolinyl optionally substituted with 1-4 R⁹. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, A is isoquinolinyl optionallysubstituted with 1-4 R⁹. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, A is pyridinyl optionally substituted with 1-4 R⁹ or A ispyridonyl optionally substituted with 1-3 R⁹. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, A is pyridinyl or pyridonyl, each of which issubstituted with 1-3 R⁹. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, A is pyridinyl substituted with 1-3 R⁹. In some embodiments ofthe compound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, A is pyridonyl substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is selected from thegroup consisting of:

each of which is optionally substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-4 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-3 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

each of which is optionally substituted with 1-2 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-2 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-2 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is

which is optionally substituted with 1-2 R⁹.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R⁹ isindependently i) halogen; ii) C₁₋₆ alkoxy optionally substituted with1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl, andC₃₋₇ monocyclic cycloalkyl; iii) —NH₂; iv) —NH(C₁₋₆ alkyl), wherein theC₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, and C₁₋₃ alkoxy; v) —N(C₁₋₆ alkyl)₂, whereineach C₁₋₆ alkyl can be the same or different, and wherein each C₁₋₆alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, and C₁₋₃ alkoxy; vi) —P(O)(C₁₋₆ alkyl)₂, wherein eachC₁₋₆ alkyl can be the same or different, and wherein each C₁₋₆ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy; vii) —S(O)₂C₁₋₆ alkyl; viii) —S(O)₂N(R²³)₂,wherein each R²³ is independently H or C₁₋₆ alkyl; ix) C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from

-   -   a) —OH,    -   b) halogen,    -   c) C₁₋₃ alkoxy,    -   d) C₃₋₇ monocyclic cycloalkyl,    -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from oxo and C₁₋₃ alkyl,        and    -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl;        x) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —OH, halogen, C₁₋₃ alkyl, and        C₁₋₃ alkoxy; xi) 5-6 membered monocyclic heteroaryl having 1-4        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heteroaryl is optionally substituted        with 1-3 groups independently selected from —OH, halogen, C₁₋₃        alkyl, and C₁₋₃ alkoxy; xii) 4-6 membered monocyclic        heterocyclyl having 1-3 heteroatoms independently selected from        N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl is        optionally substituted with 1-3 groups independently selected        from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; xiii)        —COOH; xiv) —C(O)N(R¹⁹)₂; or xv) —C₁₋₃ alkylC(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R⁹ isindependently i) a halogen; ii) C₁₋₆ alkoxy optionally substituted with1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl, andC₃₋₇ monocyclic cycloalkyl; iii) —NH₂; iv) —NH(C₁₋₃ alkyl), wherein theC₁₋₃ alkyl is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, and C₁₋₃ alkoxy; v) —N(C₁₋₃ alkyl)₂, whereineach C₁₋₃ alkyl can be the same or different, and wherein each C₁₋₃alkyl is optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, and C₁₋₃ alkoxy; vi) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; or vii) —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R⁹ isindependently i) halogen; ii) —NH₂; iii) —NH(C₁₋₃ alkyl); iv) —N(C₁₋₃alkyl)₂, wherein each C₁₋₃ alkyl is the same or different; v) C₁₋₃ alkyloptionally substituted with 1-3 groups independently selected from —OHand halogen; vi) —OCH₃ optionally substituted with 1-3 halogen groups;or vii) —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is halogen. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, or fourR⁹ is fluoro or chloro. In some embodiments ofthe compound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, or fourR⁹ is fluoro. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one, two, three, or fourR⁹ ischloro.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is C₁₋₆ alkoxy optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, or fourR⁹ is —OCH₃ optionally substituted with 1-3fluoro groups. In some embodiments of the compound of Formula I, II,IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof, one,two, three, or fourR⁹ is —OCH₃ or —OCF₃. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, or fourR⁹ is —OCH₃.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —NH₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,and C₁₋₃ alkoxy. In some embodiments of the compound of Formula I, II,IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof, one,two, three, or fourR⁹ is —NH(C₁₋₃ alkyl), wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, and C₁₋₃ alkoxy. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, one, two, three, or four R⁹ is —NH(C₁₋₃ alkyl).

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same ordifferent, and wherein each C₁₋₆ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkyl can be the same ordifferent, and wherein each C₁₋₃ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkyl is the same ordifferent. In some embodiments of the compound of Formula I, II, IIa,III, IV, or V, or a pharmaceutically acceptable salt thereof, one, two,three, or fourR⁹ is —N(CH₃)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same ordifferent, and wherein each C₁₋₆ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, one, two, three, or fourR⁹ is —P(O)(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkyl can be the same ordifferent, and wherein each C₁₋₃ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, one, two, three, orfourR⁹ is —P(O)(C₁₋₃ alkyl)₂. In some embodiments of the compound ofFormula I, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, one, two, three, or fourR⁹ is —P(O)(CH₃)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is —S(O)₂C₁₋₆ alkyl. In some embodiments of the compound ofFormula I, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, one, two, three, or four R⁹ is —S(O)₂N(R²³)₂, wherein each R²³is independently H or C₁₋₆ alkyl. In some embodiments of the compound ofFormula I, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, one, two, three, or four R⁹ is C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, or four R⁹ is 5-6 memberedmonocyclic heteroaryl having 1-4 heteroatoms independently selected fromN, O, and S, wherein the 5-6 membered monocyclic heteroaryl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, or four R⁹ is 4-6 memberedmonocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom N, O, and S, wherein the 4-6 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, or four R⁹ is —COOH.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from

-   -   a) —OH,    -   b) halogen,    -   c) C₁₋₃ alkoxy,    -   d) C₃₋₇ monocyclic cycloalkyl,    -   e) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from oxo and C₁₋₃ alkyl,        and    -   f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, or four R⁹ is C₁₋₃ alkyl optionally substituted with1-3 groups independently selected from —OH and halogen. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one, two, three, or four R⁹ ismethyl optionally substituted with 1-3 groups independently selectedfrom —OH and fluoro. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, or four R⁹ is ethyl optionally substituted with one—OH. In some embodiments of the compound of Formula I, II, IIa, III, IV,or V, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is methyl, ethyl, —CF₃, —CHF₂, —CH₂OH, or —CH(CH₃)OH. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one, two, three, or four R⁹ ismethyl or —CH₂OH.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is —C₁₋₃ alkylC(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, orfour R⁹ is —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R⁹ isindependently i) fluoro; ii) chloro; iii) methyl optionally substitutedwith 1-3 groups independently selected from —OH and fluoro; iv) ethyloptionally substituted with one —OH; v) —OCH₃ optionally substitutedwith 1-3 fluoro groups; vi) —N(CH₃)₂; or vii) —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R⁹ isindependently fluoro, chloro, methyl, ethyl, —OCH₃, —CF₃, —CHF₂, —CH₂OH,—CH(CH₃)OH, —OCF₃, —N(CH₃)₂, or —C(O)N(R¹⁹)₂. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, each R⁹ is independently fluoro, chloro,methyl, —CH₂OH, —OCH₃, —N(CH₃)₂, or —C(O)N(R¹⁹)₂.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁹ isindependently i) H; ii) —S(O)₂C₁₋₆ alkyl; iii) C₁₋₆ alkyl optionallysubstituted with 1-6 groups independently selected from —CN, —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; iv) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, C₁₋₆ alkyl, and C₁₋₆alkoxy, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy; or v)4-6 membered monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁹ isindependently i) H; ii) C₁₋₆ alkyl optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl; or iii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-6 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both R¹⁹ is H.In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one R¹⁹ is H. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, both R¹⁹ are H.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both R¹⁹ isC₁₋₆ alkyl optionally substituted with 1-6 groups independently selectedfrom —CN, —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, one or both R¹⁹ is C₁₋₄alkyl optionally substituted with 1-3 groups independently selected from—OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both R¹⁹ isC₃₋₇ monocyclic cycloalkyl optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, C₁₋₆ alkyl, and C₁₋₆alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one or both R¹⁹ is C₃₋₇monocyclic cycloalkyl optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one or both R¹⁹ is C₃₋₅monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both R¹⁹ is—S(O)₂C₁₋₆ alkyl. In some embodiments of the compound of Formula I, II,IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof, oneor both R¹⁹ is 4-6 membered monocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁹ isindependently i) H; ii) methyl; iii) ethyl optionally substituted with 1or 2 groups independently selected from —OH, fluoro, and —OCH₃; iv)n-propyl optionally substituted with 1 or 2 groups independentlyselected from fluoro and —OCH₃; V) isopropyl optionally substituted with1 or 2 fluoro groups; vi) n-butyl; vii) isobutyl optionally substitutedwith 1 or 2 fluoro groups; viii) sec-butyl; ix) tert-butyl; x)cyclopropyl optionally substituted with one methyl group, wherein themethyl is optionally substituted with 1-3 groups independently selectedfrom fluoro and —OCH₃; or xi) cyclobutyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁹ isindependently i) H; ii) methyl; iii) ethyl; iv) —CH₂CH₂OH; v)—CH₂CH₂OCH₃; vi) —CH₂CHF₂; vii) —CH₂C(CH₃)F₂; viii) n-propyl; ix)isopropyl; x) —CH(CH₃)CHF₂; xi) —CH(CH₃)CH₂F; xii) —CH(CH₂F)₂; xiii)—CH₂CH₂CHF₂; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii)—CH₂CH₂CH₂OCH₃; xviii) cyclopropyl substituted with one group selectedfrom —CH₂F, —CHF₂ and —CH₂OCH₃; or xix) cyclobutyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁹ isindependently H, methyl, isopropyl, or cyclopropyl, wherein thecyclopropyl is optionally substituted with —CH₂F.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is substituted with1-3 R⁹, and wherein each R⁹ is independently fluoro, chloro, methyl,—OCH₃, —CH₂OH, —N(CH₃)₂, —C(O)NH2, —C(O)NH(CH₃), —C(O)NH(isopropyl),

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, A is substituted with1-2 R⁹, and wherein each R⁹ is independently fluoro, chloro, methyl,—OCH₃, —CH₂OH, —N(CH₃)₂, —C(O)NH₂, —C(O)NH(CH₃),

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, R⁷ is i) H; ii) C₁₋₆alkyl optionally substituted with 1-3 groups independently selected from—OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; or iii) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, R⁷ is H.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, R⁷ is C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, R⁷ is methyl, ethyl,isopropyl, or sec-butyl. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, R⁷ is ethyl, isopropyl, or sec-butyl. In some embodiments ofthe compound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, R⁷ is isopropyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, R⁷ is C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. In some embodiments ofthe compound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, R⁷ is cyclopropyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, R⁷ is methyl, ethyl,isopropyl, sec-butyl, or cyclopropyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is NR¹⁵R¹⁶, whereinR¹⁵ and R¹⁶ are independently i) H; ii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iii) 4-7 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 4-7 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; iv) —C(O)C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1-3 groups independently selectedfrom —CN, —OH, halogen, and C₁₋₃ alkoxy; or v) C₁₋₆ alkyl optionallysubstituted with 1-6 groups independently selected from

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy,    -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —OH, halogen, C₁₋₃ alkyl, and        C₁₋₃ alkoxy, and    -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is NR¹⁵R¹⁶, whereinR¹⁵ and R¹⁶ are independently i) H; or ii) C₁₋₆ alkyl optionallysubstituted with 1-6 groups independently selected from —OH, halogen,and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵ andR¹⁶ is H. In some embodiments of the compound of Formula I, II, IIa,III, IV, or V, or a pharmaceutically acceptable salt thereof, one of R¹⁵and R¹⁶ is H.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵ andR¹⁶ is C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵ andR¹⁶ is 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatomsindependently selected from N, O, and S, wherein the 4-7 memberedmonocyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy. In some embodiments of the compound of Formula I, II, IIa, III,IV, or V, or a pharmaceutically acceptable salt thereof, one or both ofR¹⁵ and R¹⁶ is —C(O)C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, and C₁₋₃ alkoxy.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one or both of R¹⁵ andR¹⁶ is C₁₋₆ alkyl optionally substituted with 1-6 groups independentlyselected from

-   -   a) —CN,    -   b) —OH,    -   c) halogen,    -   d) C₁₋₃ alkoxy,    -   e) C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3        groups independently selected from —OH, halogen, C₁₋₃ alkyl, and        C₁₋₃ alkoxy, and    -   f) 5-6 membered monocyclic heterocyclyl having 1 or 2        heteroatoms independently selected from N, O, and S, wherein the        5-6 membered monocyclic heterocyclyl is optionally substituted        with 1-3 groups independently selected from —OH, halogen, oxo,        C₁₋₃ alkyl, and C₁₋₃ alkoxy.        In some embodiments of the compound of Formula I, II, IIa, III,        IV, or V, or a pharmaceutically acceptable salt thereof, one or        both of R¹⁵ and R¹⁶ is C₁₋₆ alkyl optionally substituted with        1-6 groups independently selected from —OH, halogen, and C₁₋₃        alkoxy. In some embodiments of the compound of Formula I, II,        IIa, III, IV, or V, or a pharmaceutically acceptable salt        thereof, one or both of R¹⁵ and R¹⁶ is C₁₋₆ alkyl optionally        substituted with 1-3 groups independently selected from —OH,        halogen, and —OCH₃. In some embodiments of the compound of        Formula I, II, IIa, III, IV, or V, or a pharmaceutically        acceptable salt thereof, one or both of R¹⁵ and R¹⁶ is i)        methyl; ii) isopropyl; iii) isobutyl optionally substituted with        one group selected from —OH, fluoro, and —OCH₃; iv) sec-butyl;        or v) C₅ alkyl optionally substituted with —OCH₃. In some        embodiments of the compound of Formula I, II, IIa, III, IV, or        V, or a pharmaceutically acceptable salt thereof, one or both of        R¹⁵ and R¹⁶ is i) methyl; ii) isopropyl; iii) isobutyl; iv)        —CH₂C(CH₃)₂F; v) —CH₂C(CH₃)₂OCH₃; vi) —CH₂C(CH₃)₂OH; vii)        sec-butyl; or viii) —CH₂C(CH₃)₂CH₂OCH₃.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, R¹⁵ and R¹⁶ areindependently i) H; ii) methyl; iii) isopropyl; iv) isobutyl optionallysubstituted with one group selected from —OH, fluoro, and —OCH₃; V)sec-butyl; or vi) C₅ alkyl optionally substituted with —OCH₃. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, R¹⁵ and R¹⁶ are independentlyi) H; ii) methyl; iii) isopropyl; iv) isobutyl; v) —CH₂C(CH₃)₂F; vi)—CH₂C(CH₃)₂OCH₃; vii) —CH₂C(CH₃)₂OH; viii) sec-butyl; or ix)—CH₂C(CH₃)₂CH₂OCH₃. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,R¹⁵ and R¹⁶ are independently H, methyl, or isobutyl, wherein theisobutyl is optionally substituted with one group selected from —OH,fluoro, and —OCH₃. In some embodiments of the compound of Formula I, II,IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof, oneof R¹⁵ and R¹⁶ is H or methyl and the other of R¹⁵ and R¹⁶ is isobutyloptionally substituted with one group selected from —OH, fluoro, and—OCH₃. In some embodiments of the compound of Formula I, II, IIa, III,IV, or V, or a pharmaceutically acceptable salt thereof, R¹⁵ and R¹⁶ areindependently H, methyl, isobutyl, —CH₂C(CH₃)₂OCH₃, CH₂C(CH₃)₂OH, orCH₂C(CH₃)₂F.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is a 4-10 memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl having 1-3 heteroatoms independently selected from N, O,and S, wherein the 4-10 membered monocyclic, fused bicyclic, bridgedbicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is a 4-9 memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl having 1-3 heteroatoms independently selected from N, O,and S, wherein the 4-9 membered monocyclic, fused bicyclic, bridgedbicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-5 R¹⁸. As used herein,

is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, orspirocyclic heterocyclyl with at least one nitrogen ring atom, whereinthe nitrogen ring atom is the point of attachment for the 4-10 memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is azetidinyl,pyrrolidinyl, piperidinyl, or morpholinyl, each of which is optionallysubstituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is azetidinyloptionally substituted with 1-4 R¹⁸. In some embodiments of the compoundof Formula I, II, IIa, III, IV, or V, or a pharmaceutically acceptablesalt thereof, X is azetidinyl optionally substituted with 1-3 R¹⁸. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, X is azetidinyloptionally substituted with 1-2 R¹⁸. In some embodiments of the compoundof Formula I, II, IIa, III, IV, or V, or a pharmaceutically acceptablesalt thereof, X is pyrrolidinyl optionally substituted with 1-5 R¹⁸. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, X is piperidinyloptionally substituted with 1-5 R¹⁸. In some embodiments of the compoundof Formula I, II, IIa, III, IV, or V, or a pharmaceutically acceptablesalt thereof, X is morpholinyl optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-5 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-4 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

each of which is optionally substituted with 1-3 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-4 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-3 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-4 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

which is optionally substituted with 1-3 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is unsubstituted. Insome embodiments of the compound of Formula I, II, IIa, III, IV, or V,or a pharmaceutically acceptable salt thereof, X is substituted with 1-5R¹⁸. In some embodiments of the compound of Formula I, II, IIa, III, IV,or V, or a pharmaceutically acceptable salt thereof, X is substitutedwith 1-4 R¹⁸. In some embodiments of the compound of Formula I, II, IIa,III, IV, or V, or a pharmaceutically acceptable salt thereof, X issubstituted with 1-3 R¹⁸. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, X is substituted with 1-2 R¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is substituted withone R¹⁸. In some embodiments of the compound of Formula I, II, IIa, III,IV, or V, or a pharmaceutically acceptable salt thereof, X issubstituted with two R¹⁸. In some embodiments of the compound of FormulaI, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, X is substituted with three R¹⁸. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, X is substituted with four R¹⁸. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, X is substituted with fiveR¹⁸.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, two R¹⁸ are attachedto the same carbon.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁸ isindependently i) —CN; ii) a halogen; iii) —OH; iv) C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; v) C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; vi) —COOH; or vii)—C(O)N(R²²)₂, wherein each R²² is independently H or C₁₋₆ alkyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁸ isindependently i) a halogen; ii) —OH; or iii) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁸ isindependently —OH, fluoro, or C₁₋₃ alkyl optionally substituted with 1-3groups independently selected from —OH and halogen.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, each R¹⁸ isindependently —OH, fluoro, or methyl optionally substituted with 1-3groups independently selected from —OH and fluoro.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, four,or five R¹⁸ is —CN. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, four, or five R¹⁸ is a halogen. In some embodiments ofthe compound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, four, or five R¹⁸ is fluoro.In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, four,or five R¹⁸ is —OH. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, four, or five R¹⁸ is —COOH. In some embodiments of thecompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof, one, two, three, four, or five R¹⁸ is—C(O)N(R²²)₂, wherein each R²² is independently H or C₁₋₆ alkyl. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one, two, three, four, or fiveR¹⁸ is C₁₋₆ alkoxy optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, four,or five R¹⁸ is C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl. In some embodiments of the compound of Formula I,II, IIa, III, IV, or V, or a pharmaceutically acceptable salt thereof,one, two, three, four, or five R¹⁸ is C₁₋₃ alkyl optionally substitutedwith 1-3 groups independently selected from —OH and halogen. In someembodiments of the compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof, one, two, three, four, or fiveR¹⁸ is a methyl optionally substituted with 1-3 groups independentlyselected from —OH and fluoro. In some embodiments of the compound ofFormula I, II, IIa, III, IV, or V, or a pharmaceutically acceptable saltthereof, one, two, three, four, or five R¹⁸ is a methyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, one, two, three, four,or five R¹⁸ is fluoro or methyl.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, or a pharmaceutically acceptable salt thereof, X is

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IVthe compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, IV, orV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, III, or IV,the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I, II, IIa, or III, thecompound is:

or a pharmaceutically acceptable salt thereof.

III. Compositions and Kits

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that comprise one or more of the compoundsprovided herein or pharmaceutically acceptable salts, isomer, or amixture thereof and one or more pharmaceutically acceptable vehiclesselected from carriers, adjuvants and excipients. The compounds providedherein may be the sole active ingredient or one of the activeingredients of the pharmaceutical compositions. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants. Such compositions are prepared in a manner well known in thepharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes,Eds.).

In one aspect, provided herein are pharmaceutical compositionscomprising a compound provided herein (e.g., a compound of Formula I,II, IIa, III, VI, or V), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient or carrier. In someembodiments, the pharmaceutical compositions comprise a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient orcarrier.

In some embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more (e.g., one, two, three, four, one or two,one to three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions further comprise a therapeutically effectiveamount of the one or more (e.g., one, two, three, four, one or two, oneto three, or one to four) additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for a hepatitis B virus (HBV)infection, human immunodeficiency virus (HIV) infection, cancer, or ahyper-proliferative disease. In some embodiments, the one or moreadditional therapeutic agents include PD1 inhibitors and/or PDL1inhibitors. In some embodiments, the one or more additional therapeuticagents that are therapeutic for HBV infection include PDL1 inhibitorsand/or PDL1 inhibitors. In some embodiments, the one or more additionaltherapeutic agents that are therapeutic for cancer orhyper-proliferative disease include PD1 inhibitors and/or PDL1inhibitors.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for HBV infection. In someembodiments, the one or more additional therapeutic agents is selectedfrom the group consisting of: adefovir (Hepsera®), tenofovir disoproxilfumarate+emtricitabine (Truvada®), tenofovir disoproxil fumarate(Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®),Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1(Humoferon®), ribavirin, interferon beta-1a (Avonex®),Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide,Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferonalfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg,Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for HIV infection. In someembodiments, the one or more additional therapeutic agents is selectedfrom the group consisting of: 4′-ethynyl-2-fluoro-2′-deoxyadenosine,bictegravir or a pharmaceutically acceptable salt thereof, abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofoviralafenamide hemifumarate, emtricitabine, and lamivudine, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude PD1 inhibitors and/or PDL1 inhibitors. In some embodiments, theone or more additional therapeutic agents is selected from the groupconsisting of: nivolumab, lambrolizumab, pembrolizumab, pidilizumab,PDR001, TSR-001, atezolizumab, durvalumab, or avelumab, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agentsinclude agents that are therapeutic for cancer or hyper-proliferativedisease. In some embodiments, the one or more additional therapeuticagents is selected from the group consisting of: rituxan, doxorubicin,gemcitabine, pidilizumab, TSR-042, BMS-986016, ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319,GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145,IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117,WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TGI00115, IC87114,IPI-549, INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical compositions may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In some embodiments, the pharmaceutical compositionsmay be administered by intra-arterial injection, intravenously,intraperitoneally, parenterally, intramuscularly, subcutaneously,orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds provided herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound provided herein orpharmaceutically acceptable salts, isomer, or a mixture thereof, theactive ingredient (such as a compound provided herein) is usuallydiluted by an excipient and/or enclosed within such a carrier that canbe in the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be in the form of a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the pharmaceutical compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing, for example,up to 10% by weight of the active compound, soft and hard gelatincapsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose or any combinations thereof. The pharmaceutical compositionscan additionally include lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl and propylhydroxy-benzoates;sweetening agents; and flavoring agents; or any combinations thereof.

The pharmaceutical compositions that include at least one compounddescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof can be formulated so as to provide quick, sustained ordelayed release of the active ingredient (such as a compound providedherein) after administration to the subject by employing proceduresknown in the art. Controlled release drug delivery systems for oraladministration include osmotic pump systems and dissolutional systemscontaining polymer-coated reservoirs or drug-polymer matrixformulations. Examples of controlled release systems are given in U.S.Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Anotherformulation for use in the methods of the present disclosure employstransdermal delivery devices (“patches”). Such transdermal patches maybe used to provide continuous or discontinuous infusion of the compoundsprovided herein in controlled amounts. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or pharmaceutically acceptable salts, isomer,or a mixture thereof. When referring to these preformulationcompositions as homogeneous, the active ingredient may be dispersedevenly throughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with materials such as shellac, cetyl alcohol, andcellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. In some embodiments, the compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. In other embodiments, compositions in pharmaceuticallyacceptable solvents may be nebulized by use of inert gases. Nebulizedsolutions may be inhaled directly from the nebulizing device or thenebulizing device may be attached to a facemask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, fromdevices that deliver the formulation in an appropriate manner.

In one aspect, provided herein are kits that comprise a compoundprovided herein, (e.g., a compound of Formula I, II, IIa, III, IV, orV), or a pharmaceutically acceptable salt, stereoisomer, prodrug, orsolvate thereof, and suitable packaging. In some embodiments, the kitfurther comprises instructions for use. In some embodiments, the kitcomprises a compound provided herein (e.g., a compound of Formula I, II,IIa, III, IV, or V), or a pharmaceutically acceptable salt,stereoisomer, prodrug, or solvate thereof, and a label and/orinstructions for use of the compounds in the treatment of theindications, including the diseases or conditions, described herein.

In some embodiments, the kits further comprise one or more (e.g., one,two, three, four, one or two, one to three, or one to four) additionaltherapeutic agents, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are articles of manufacture that comprisea compound described herein or pharmaceutically acceptable salts,isomer, or a mixture thereof in a suitable container. In someembodiments, the container may be a vial, jar, ampoule, preloadedsyringe, or intravenous bag.

IV. Methods

The methods provided herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods provided herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. Exemplary tissue samples includetumors and biopsies thereof. In this context, the present disclosure maybe used for a variety of purposes, including therapeutic andexperimental purposes. For example, the present disclosure may be usedex vivo to determine the optimal schedule and/or dosing ofadministration of a HPK1 inhibitor for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the present disclosuremay be suited are described below or will become apparent to thoseskilled in the art. The selected compounds may be further characterizedto examine the safety or tolerance dosage in human or non-humansubjects. Such properties may be examined using commonly known methodsto those skilled in the art.

In one aspect, the present disclosure provides methods of inhibitingHPK1 activity in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, II, IIa, III, IV, or V), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treating adisease or disorder associated with increased HPK1 activity in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of increasingT-cell activation in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound providedherein (e.g., a compound of Formula I, II, IIa, III, IV, or V), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In one aspect, the present disclosure provides methods of treatingcancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound provided herein(e.g., a compound of Formula I, II, IIa, III, IV, or V), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition provided herein.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma,urothelial cancer. In some embodiments, the cancer is a solid tumor.

In one aspect, the present disclosure provides methods of inhibiting thegrowth or proliferation of cancer cells in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g, a compound of Formula I, II,IIa, III, IV, or V), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition provided herein.

In some embodiments, the above methods further comprise administering atherapeutically effective amount of one or more additional therapeuticagents, or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: Inducible T-cell costimulator(ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blockingantibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47(CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8)agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors,lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors,V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation(VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors,STING agonists, C-X-C chemokine receptor type 4 (CXCR-4) inhibitors,B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusionproteins, MKNK1/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: rituxan, doxorubicin,gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001,atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016,ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH₅₁₃₂₇₉₉, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319,GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145,IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117,WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114,IPI-549, INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

In one aspect, the present disclosure provides methods of treating orpreventing a hepatitis B virus (HBV) infection in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (e.g., a compound ofFormula I, II, IIa, III, IV, or V), or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition provided herein.

In some embodiments, the method of treating or preventing a HBVinfection further comprises administering a therapeutically effectiveamount of one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HBV combination drugs, HBVvaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-likereceptor (TLR) modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg)inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton'styrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replicationinhibitors, arginase inhibitors, and other HBV drugs, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of entecavir, adefovir, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine and lamivudine, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of tenofovir alafenamide, tenofoviralafenamide fumarate, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In one aspect, the present disclosure provides methods of treating orpreventing a human immunodeficiency virus (HIV) infection in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound provided herein (e.g., acompound of Formula I, II, IIa, III, IV, or V), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition providedherein.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering a therapeutically effectiveamount of one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, tenofovir alafenamide fumarate and tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovirdisoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxilfumarate, or a pharmaceutically acceptable salt of any of the foregoing,or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents isselected from the group consisting of emtricitabine and lamivudine, or apharmaceutically acceptable salt of each thereof.

In some embodiments, the one or more additional therapeutic agents isemtricitabine or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovir, tenofovirdisoproxil, tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, tenofovir alafenamide, and tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof, and further comprisesadministering another therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine, or a pharmaceuticallyacceptable salt of each thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof, and further comprises administering anothertherapeutic agent selected from the group consisting of emtricitabineand lamivudine, or a pharmaceutically acceptable salt of each thereof.

In some embodiments, the method of treating or preventing a HIVinfection further comprises administering one or more additionaltherapeutic agents selected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofovirdisoproxil, tenofovir disoproxil fumarate, and tenofovir disoproxilhemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof, and further comprisesadministering another therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the methods described herein comprise administeringa therapeutically effective amount of a compound provided herein (e.g.,a compound of Formula I, II, IIa, III, IV, or V), or a pharmaceuticallyacceptable salt thereof. In some embodiments, the methods describedherein comprise administering a therapeutically effective amount of apharmaceutical composition provided herein.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in therapy.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofinhibiting hematopoietic progenitor kinase 1 (HPK1) activity in asubject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating a disease or disorder associated with increased hematopoieticprogenitor kinase 1 (HPK1) activity in a subject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofincreasing T-cell activation in a subject in need thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating cancer in a subject in need thereof.

In some embodiments, the cancer is selected from the group consisting ofbladder cancer, breast cancer, colorectal cancer, gastric cancer, headand neck squamous cell carcinoma, Hodgkin lymphoma, Merkel-cellcarcinoma, mesothelioma, melanoma, non-small cell lung cancer, lungcancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cellcarcinoma, small cell lung cancer, transitional cell carcinoma, andurothelial cancer. In some embodiments, the cancer is a solid tumor.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method ofinhibiting the growth or proliferation of cancer cells in a subject inneed thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering a therapeutically effective amount of one ormore additional therapeutic agents, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: Inducible T-cell costimulator(ICOS) agonists, cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blockingantibodies, PD1 and/or PD-L1 inhibitors, Cluster of Differentiation 47(CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8)agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors,lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, Tcell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors,V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation(VISTA) inhibitors, anti-Killer IgG-like receptors (KIR) inhibitors,STING agonists, C-X-C chemokine receptor type 4 (CXCR-4) inhibitors,B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusionproteins, MKNK1/2 inhibitors, JAK inhibitors, and PI3K inhibitors, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: rituxan, doxorubicin,gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001,atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016,ruxolitinib,N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide,XL147, BKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235,and GDC-0980, wortmannin, LY294002, TGR-1202, AMG-319, GSK2269557,X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443,GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037,AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549,INCB050465,(S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one,(S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one,(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,and ipilimumab, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the use in a method of inhibiting the growth orproliferation of cancer cells in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of idelalisib, tirabrutinib,momelotinib, and entospletinib, or a pharmaceutically acceptable salt ofany of the foregoing, or any combinations thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing a hepatitis B virus (HBV) infection in a subjectin need thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering a therapeutically effective amount of one ormore additional therapeutic agents, or a pharmaceutically acceptablethereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of HBV combination drugs, HBVvaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-likereceptor (TLR) modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg)inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucelotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton'styrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replicationinhibitors, arginase inhibitors, and other HBV drugs, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of adefovir (Hepsera®), tenofovirdisoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxilfumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine(Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b(PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferonalpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®),interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a(Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A,Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone,interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum,Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion,Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure,PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b,Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b,Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant humaninterleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang ShengLei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of entecavir, adefovir, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovirdisoproxil, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, telbivudine and lamivudine, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of tenofovir alafenamide, tenofoviralafenamide fumarate, and tenofovir alafenamide hemifumarate, or apharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In one aspect, provided herein is a compound disclosed herein, or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing a human immunodeficiency virus (HIV) infection ina subject in need thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agents, or apharmaceutically acceptable salt thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of: combination drugs for HIV, otherdrugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, latency reversingagents, compounds that target the HIV capsid, immune-based therapies,phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies,bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-transisomerase A modulators, protein disulfide isomerase inhibitors,complement C5a receptor antagonists, DNA methyltransferase inhibitor,HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,integrin antagonists, nucleoprotein inhibitors, splicing factormodulators, COMM domain containing protein 1 modulators, HIVribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,or a pharmaceutically acceptable salt of any of the foregoing, or anycombinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, abacavir sulfate,tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, or a pharmaceutically acceptable salt of anyof the foregoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir, tenofoviralafenamide, tenofovir alafenamide fumarate or tenofovir alafenamidehemifumarate, or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof.

In some embodiments, the use in a method of treating or preventing ahepatitis B virus (HBV) infection in a subject in need thereof furthercomprises administering one or more additional therapeutic agentsselected from the group consisting of4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir or a pharmaceuticallyacceptable salt thereof, tenofovir disoproxil, tenofovir disoproxilhemifumarate or tenofovir disoproxil fumarate, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combinations thereof.

In some embodiments, the uses described herein comprise administering atherapeutically effective amount of a compound provided herein (e.g., acompound of Formula I, II, IIa, III, IV, or V), or a pharmaceuticallyacceptable salt thereof.

V. Administration

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with, for example, thecondition of the recipient. An advantage of certain compounds disclosedherein is that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In some embodiments, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The specific dose level of a compound of the present disclosure for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt or pharmaceutically acceptable tautomer thereof, may bebetween about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day,between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day,between about 10 to 500 mg/day, between about 20 to 500 mg/day, betweenabout 50 to 300 mg/day, between about 75 to 200 mg/day, or between about15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compounds of the present disclosure may be administered to anindividual (e.g., a human) in a therapeutically effective amount. Insome embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful routeand means, such as by oral or parenteral (e.g., intravenous)administration. Therapeutically effective amounts of the compound mayinclude from about 0.00001 mg/kg body weight per day to about 10 mg/kgbody weight per day, such as from about 0.0001 mg/kg body weight per dayto about 10 mg/kg body weight per day, or such as from about 0.001 mg/kgbody weight per day to about 1 mg/kg body weight per day, or such asfrom about 0.01 mg/kg body weight per day to about 1 mg/kg body weightper day, or such as from about 0.05 mg/kg body weight per day to about0.5 mg/kg body weight per day. In some embodiments, a therapeuticallyeffective amount of the compounds provided herein include from about 0.3mg to about 30 mg per day, or from about 30 mg to about 300 mg per day,or from about 0.3 μg to about 30 mg per day, or from about 30 μg toabout 300 μg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 0.1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose, orsuch as from about 0.01 mg per dose to about 1000 mg per dose, or suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose, or such as from about 1 mg per dose toabout 1000 mg per dose. Other therapeutically effective amounts of thecompound of Formula I, II, IIa, III, IV, or V are about 1 mg per dose,or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Othertherapeutically effective amounts of the compound of the presentdisclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325,350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675,700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about1000 mg per dose.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundp herein and increasing the dose by increments until clinical efficacyis achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used toincrease the dose. The dosage can be increased daily, every other day,twice per week, once per week, once every two weeks, once every threeweeks, or once a month.

When administered orally, the total daily dosage for a human subject maybe between about 1 mg and 1,000 mg, between about 10-500 mg/day, betweenabout 50-300 mg/day, between about 75-200 mg/day, or between about100-150 mg/day. In some embodiments, the total daily dosage for a humansubject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or1000 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 200, 300, 400, 500,600, 700, or 800 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about300, 400, 500, or 600 mg/day administered in a single dose.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce daily in a method disclosed herein. In some embodiments, a compounddisclosed herein is administered twice daily in a method disclosedherein.

The frequency of dosage of the compound of the present disclosure willbe determined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the HBVinfection, HIV infection, cancer, hyper-proliferative disease, or anyother indication described herein. For example, a compound can beadministered to a human being infected with HBV for a period of from 20days to 180 days or, for example, for a period of from 20 days to 90days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from 1 to 14 days,followed by a period of 7 to 21 days during which the patient does notreceive a dose of the compound, followed by a subsequent period (e.g.,from 1 to 14 days) during which the patient again receives a daily doseof the compound. Alternating periods of administration of the compound,followed by non-administration of the compound, can be repeated asclinically required to treat the patient.

The compounds of the present disclosure or the pharmaceuticalcompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above. Also,administration or treatment with the compounds may be continued for anumber of days; for example, commonly treatment would continue for atleast 7 days, 14 days, or 28 days, for one cycle of treatment. Treatmentcycles are well known in cancer chemotherapy, and are frequentlyalternated with resting periods of about 1 to 28 days, commonly about 7days or about 14 days, between cycles. The treatment cycles, in otherembodiments, may also be continuous.

VI. Combination Therapy

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In some embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two additional therapeutic agents. Insome embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In some embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In some embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In some embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In some embodiments, a compound of the present disclosure isco-administered with one or more additional therapeutic agents.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. The compoundsdisclosed herein may be administered within seconds, minutes, or hoursof the administration of one or more additional therapeutic agents. Forexample, in some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, in other embodiments, a unit dose of one or moreadditional therapeutic agents is administered first, followed byadministration of a unit dose of a compound disclosed herein withinseconds or minutes. In some embodiments, a unit dose of a compounddisclosed herein is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of one ormore additional therapeutic agents. In other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

In some embodiments a compound of Formula I, II, IIa, III, IV, or V, isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating the disease being treated. In certainembodiments, the tablet can contain another active ingredient fortreating a HBV infection, HIV infection, cancer, or ahyper-proliferative disease. In some embodiments, such tablets aresuitable for once daily dosing

Also provided herein are methods of treatment in which a compound ofFormula I, II, IIa, III, IV, or V, or a tautomer or pharmaceuticallyacceptable salt thereof, is given to a patient in combination with oneor more additional therapeutic agents or therapy. In some embodiments,the total daily dosage of a compound of Formula I, II, IIa, III, IV, orV, or a tautomer, or a pharmaceutically acceptable salt thereof, may beabout 300 mg/day administered in a single dose for a human subject.

HBV Combination Therapy

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, one tothree, or one to four) additional therapeutic agents. In one embodiment,a method for treating an HBV infection in a human having or at risk ofhaving the infection is provided, comprising administering to the humana therapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three, or one to four) additional therapeuticagents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents which are suitable for treating an HBV infection.

The compounds described herein may be used or combined with one or moreof a chemotherapeutic agent, an immunomodulator, an immunotherapeuticagent, a therapeutic antibody, a therapeutic vaccine, a bispecificantibody and “antibody-like” therapeutic protein (such as DARTs®,Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drugconjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9,zinc finger nucleases, homing endonucleases, synthetic nucleases,TALENs), cell therapies such as CAR-T (chimeric antigen receptorT-cell), and TCR-T (an engineered T cell receptor) agent or anycombination thereof.

In certain embodiments, a compound of Formula (J) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV, such as 3-dioxygenase (IDO)inhibitors, Apolipoprotein A1 modulator, arginase inhibitors, B- andT-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK)inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160inhibitors, CD305 inhibitors, CD4 agonist and modulator, compoundstargeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg),core protein allosteric modulators, covalently closed circular DNA(cccDNA) inhibitors, cyclophilin inhibitors, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, HBsAg inhibitors, HBsAg secretion or assemblyinhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors,HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors,Hepatitis B large envelope protein modulator, Hepatitis B large envelopeprotein stimulator, Hepatitis B structural protein modulator, hepatitisB surface antigen (HBsAg) inhibitors, hepatitis B surface antigen(HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotidereductase, Interleukin-2 ligand, ipi4 inhibitors, lysine demethylaseinhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5inhibitors, killer cell lectin-like receptor subfamily G member 1inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin betareceptor activators, modulators of Ax1, modulators of B7-H3, modulatorsof B7-H4, modulators of CD160, modulators of CD161, modulators of CD27,modulators of CD47, modulators of CD70, modulators of GITR, modulatorsof HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A,modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,modulators of TIGIT, modulators of Tim-4, modulators of Tyro,Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, naturalkiller cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoproteininhibitor, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors,Peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K)inhibitors, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, and combinations thereof.

HBV Combination Drugs

Examples of combination drugs for the treatment of HBV include TRUVADA®(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine,and PEG-IFN-alpha; ABX-203 adefovir, and PEG-IFNalpha; and INO-1800(INO-9112 and RG7944).

Other HBV Drugs

Examples of other drugs for the treatment of HBV includealpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides,AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin(gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047,NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-0061A,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551,and ZH-2N, and the compounds disclosed in US20150210682 (Roche), US2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche),WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche),WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche),WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), andUS2015031687A (Roche).

HBV Vaccines

HBV vaccines include both prophylactic and therapeutic vaccines.Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), recombinant hepatitis Bsurface antigen vaccine, Bimmugen, Euforavac, Eutravac,anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAGvaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa, and DTaP-rHB-Hibvaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex,ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay,GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC(NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2,CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500,HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine,HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine(HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,ChronVac-B, TG-1050, and Lm HBV.

HBV DNA Polymerase Inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®),emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovirdipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethylester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate,telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine, ribavirin,lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir,SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxilaspartate, tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidol hydrochloride,ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin,hydroxyurea, mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF), JNJ-440,WF-10,AB-452, ribavirin, IL-12,INO-9112, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22,CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559,GS-9688, RO-7011785,RG-7854, AB-506, RO-6871765, AIC-649, and IR-103.

Toll-Like Receptor (TLR) Modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim,RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620 (vesatolimod), GSK-2245035,imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197,3M-051, SB-9922, 3M-052, Limtop, D, telratolimod, SP-0509, TMX-30X,TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and the compounds disclosedin US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), andUS20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688 and the compoundsdisclosed in US20140045849 (Janssen), US20140073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),US20080234251 (Array Biopharma), US20080306050 (Array Biopharma),US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics),US20130251673 (Novira Therapeutics), U.S. Pat. No. 9,670,205,US20160289229, U.S. patent application Ser. No. 15/692,161, and U.S.patent application Ser. No. 15/692,093.

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055,IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054,DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, andCYT-003-QbG10.

Examples of TLR7, TLR8 and TLR9 modulators include the compoundsdisclosed in WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen),WO2018045150 (Gilead Sciences Inc.), WO2018045144 (Gilead SciencesInc.), WO2015162075 (Roche), WO2017034986 (University of Kansas),WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche),WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche),WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279(Novartis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo(Shanghai) Pharmaceutical), WO2017106607 (Merck), WO2017061532 (SumitomoDainippon Pharma), WO2016023511 (Chia Tai Tianqing Pharmaceutical),WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche),WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (GileadSciences), WO2018049089 (BristolMyers Squibb),WO2015057655 (Eisai CoLtd), WO2017001307 (Roche), WO2018005586 (BristolMyers Squibb),WO201704023(3M Co), WO2017163264 (Council of Scientific and IndustrialResearch (India)), WO2018046460 (GlaxoSmithKline Biologicals),WO2018047081 (Novartis), WO2016142250 (Roche), WO2015168269 (Novartis),WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd),WO2017202704 (Roche), WO2018026620 (BristolMyers Squibb), WO2016029077(Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche),WO2017190669 (Shanghai De Novo Pharmatech), U.S. Ser. No. 09/884,866(University of Minnesota), WO2017219931 (Sichuan KelunBiotechBiopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054(Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics),WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical),WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University ofKansas), WO2015023958 (University of Kansas)

Interferon Alpha Receptor Ligands

Examples of interferon alpha receptor ligands include interferonalpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®),PEGylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound interferon), Ypeginterferon alfa-2b(YPEG-rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®),Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-n1(HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alfa-2b(Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon,interferon alfa-2b (Amega), interferon alfa-2b (Virchow),ropeginterferon alfa-2b, rHSA-IFN alpha-2a (recombinant human serumalbumin intereferon alpha 2a fusion protein), rHSA-IFN alpha 2b,recombinant human interferon alpha-(1b, 2a, 2b), peginterferon alfa-2b(Amega), peginterferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon,Urifron, interferon alfa-2b (Changchun Institute of BiologicalProducts), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, SFR-9216, andInterapo (Interapa).

Hyaluronidase Inhibitors

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15,PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165,REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, andREP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4) Inhibitors

Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept,PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cyclophilin Inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030,SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosedin U.S. Pat. No. 8,513,184 (Gilead Sciences), US20140030221 (GileadSciences), US20130344030 (Gilead Sciences), and US20130344029 (GileadSciences).

HBV Viral Entry Inhibitors

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

Examples of antisense oligonucleotide targeting viral mRNA includeISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

Short Interfering RNAs (siRNA) and ddRNAi

Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008,HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

Examples of endonuclease modulators include PGN-514.

Ribonucelotide Reductase Inhibitors

Examples of inhibitors of ribonucleotide reductase include Trimidox.

HBV E Antigen Inhibitors

Examples of HBV E antigen inhibitors include wogonin.

Covalently Closed Circular DNA (cccDNA) Inhibitors

Examples of cccDNA inhibitors include BSBI-25, and CHR-101.

Farnesoid X receptor agonist

Examples of farnesoid x receptor agonist such as EYP-001, GS-9674,EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3,NTX-023-1, EP-024297 and GS-8670

HBV Antibodies

Examples of HBV antibodies targeting the surface antigens of thehepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV HepabulinSN, and fully human monoclonal antibody therapy (hepatitis B virusinfection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal antibodies andpolyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies include HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

Examples of thymosin agonists include Thymalfasin, recombinant thymosinalpha 1 (GeneScience)

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2(IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),IL-15, IL-21, IL-24, and celmoleukin.

Nucleoprotein Modulators

Nucleoprotein modulators may be either HBV core or capsid proteininhibitors. Examples of nucleoprotein modulators include GS-4882,AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109,morphothiadine mesilate, ARB-168786, ARB-880, JNJ-379, RG-7907,HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23.

Examples of capsid inhibitors include the compounds disclosed inUS20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US20140343032 (Roche), WO2014037480 (Roche),US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen),WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen),WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen),WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira),US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira),US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira),US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira), WO2014184350(Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882(Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395(Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881(Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160(Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941(Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen),WO2016168619 (Indiana University), WO2016195982 (The Penn StateFoundation), WO2017001655 (Janssen), WO2017048950 (AssemblyBiosciences), WO2017048954 (Assembly Biosciences), WO2017048962(Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

Examples of transcript inhibitors include the compounds disclosed inWO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche),WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655(Roche), WO2016161268 (Enanta), WO2017001853 (Redex Pharma),WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis),WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma),US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).

Retinoic Acid-Inducible Gene 1 Stimulators

Examples of stimulators of retinoic acid-inducible gene 1 includeSB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198,and ORI-7170, RGT-100.

NOD2 Stimulators

Examples of stimulators of NOD2 include SB-9200.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186,AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib,rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib,IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584,copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093,pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414,SAR-260301,TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2, 3-Dioxygenase (IDO) Pathway Inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat(4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028,GBV-1012, NKTR-218, and the compounds disclosed in US20100015178(Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (FlexusBiosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

PD-1 Inhibitors

Examples of PD-1 inhibitors include cemiplimab, nivolumab,pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001,PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA-170,durvalumab, atezolizumab and mDX-400, JS-001, Camrelizumab, Sintilimab,Sintilimab, tislelizumab, BCD-100, BGB-A333 JNJ-63723283, GLS-010(WBP-3055), CX-072, AGEN-2034, GNS-1480 (Epidermal growth factorreceptor antagonist; Programmed cell death ligand 1 inhibitor), CS-1001,M-7824 (PD-L1/TGF-β bifunctional fusion protein), Genolimzumab,BMS-936559.

PD-L1 Inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224,MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C,TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.

Examples of PD-1 inhibitors include the compounds disclosed inWO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624,WO2014151634 (BristolMyers Squibb Co), WO201317322 (BristolMyers SquibbCo), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp),WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp), WO2018119221(Incyte Corp), WO2018118848 (BristolMyers Squibb Co), WO20161266460(BristolMyers Squibb Co), WO2017087678 (BristolMyers Squibb Co),WO2016149351 (BristolMyers Squibb Co), WO2015033299 (Aurigene DiscoveryTechnologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai ResearchInstitute), WO2017066227 (BristolMyers Squibb Co), WO2016142886(Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene DiscoveryTechnologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd;Individual), WO2016142833 (Aurigene Discovery Technologies Ltd),WO2018085750 (BristolMyers Squibb Co), WO2015033303 (Aurigene DiscoveryTechnologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co;Individual; Texas A&M University System), WO2015160641 (BristolMyersSquibb Co), WO2017079669 (Incyte Corp), WO2015033301 (Aurigene DiscoveryTechnologies Ltd), WO2015034820 (BristolMyers Squibb Co), WO2018073754(Aurigene Discovery Technologies Ltd), WO2016077518 (BristolMyers SquibbCo), WO2016057624 (BristolMyers Squibb Co), WO2018044783 (Incyte Corp),WO2016100608 (BristolMyers Squibb Co), WO2016100285 (BristolMyers SquibbCo), WO2016039749 (BristolMyers Squibb Co), WO2015019284 (CambridgeEnterprise Ltd), WO2016142894 (Aurigene Discovery Technologies Ltd),WO2015134605 (BristolMyers Squibb Co), WO2018051255 (Aurigene DiscoveryTechnologies Ltd), WO2018051254 (Aurigene Discovery Technologies Ltd),WO2017222976 (Incyte Corp), WO2017070089 (Incyte Corp), WO2018044963(BristolMyers Squibb Co), WO2013144704 (Aurigene Discovery TechnologiesLtd), WO2018013789 (Incyte Corp), WO2017176608 (BristolMyers Squibb Co),WO2018009505 (BristolMyers Squibb Co), WO2011161699 (Aurigene DiscoveryTechnologies Ltd), WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp),WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317(Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene DiscoveryTechnologies Ltd), WO2015036927 (Aurigene Discovery Technologies Ltd),WO2015044900 (Aurigene Discovery Technologies Ltd), WO2018026971(Arising International).

Other examples of PD-1 and/or PDL-1 inhibitors include the compoundsdisclosed in U.S. Provisional Ser. Nos. 62/630,187, 62/640534,62/736,116, and 62/747,029.

Recombinant Thymosin Alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylatedthymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196),ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062,ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058,RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536,M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015(Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), andUS20130217880 (Ono Pharmaceutical).

KDM Inhibitors

Examples of KDM5 inhibitors include the compounds disclosed inWO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in U.S. Pat.No. 9,186,337B2 (Oryzon Genomics), GSK-2879552, and RG-6016.

STING Agonists

Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX, andthe compounds disclosed in WO 2018065360 (Biolog Life Science InstituteForschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466(Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (ImmuneSensor), WO 2017106740 (Aduro Biotech), US 20170158724 (GlaxoSmithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO2014179760 (University of California), WO2018098203 (Janssn),WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda),WO2018067423 (Merck), WO2018060323 (Boehringer).

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Examples of NNRTI include the compounds disclosed in WO2018118826(Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108(Idenix), WO2017027434 (Merck), WO2017007701 (Merck), WO2008005555(Gilead).

HBV Replication Inhibitors

Examples of hepatitis B virus replication inhibitors includeisothiafludine, IQP-HBV, RM-5038, and Xingantie.

Arginase Inhibitors

Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

Gene Therapy and Cell Therapy

Gene therapy and cell therapy includes the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; and genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Gene Editors

Examples of genome editing systems include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system; e.g., cccDNA elimination via targetedcleavage, and altering one or more of the hepatitis B virus (HBV) viralgenes. Altering (e.g., knocking out and/or knocking down) the PreC, C,X, PreSI, PreS2, S, P or SP gene refers to (1) reducing or eliminatingPreC, C, X, PreSI, PreS2, S, P or SP gene expression, (2) interferingwith Precore, Core, X protein, Long surface protein, middle surfaceprotein, S protein (also known as HBs antigen and HBsAg), polymeraseprotein, and/or Hepatitis B spliced protein function (HBe, HBc, HBx,PreSI, PreS2, S, Pol, and/or HBSP or (3) reducing or eliminating theintracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx,LHBs, MHBs, SHBs, Pol, and/or HBSP proteins. Knockdown of one or more ofthe PreC, C, X PreSI, PreS2, S, P and/or SP gene(s) is performed bytargeting the gene(s) within HBV cccDNA and/or integrated HBV DNA.

CAR-T Cell Therapy

CAR T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises an HBV antigen-binding domain. The immune effector cell is a Tcell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, aCD8+ T cell, or a combination thereof. Cells can be autologous orallogeneic.

TCR-T Cell Therapy

TCR T cell therapy includes T cells expressing HBV-specific T cellreceptors. TCR-T cells are engineered to target HBV derived peptidespresented on the surface of virus-infected cells. In some embodiments,the T-cells express HBV surface antigen (HBsAg)-specific TCR. Examplesof TCR-T therapy directed to treatment of HBV include LTCR-H2-1.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of immunomodulators, TLR modulators, HBsAginhibitors, HBsAg secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors,Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from thegroup consisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, siRNA, miRNA gene therapy agents,sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core orcapsid protein modulators).

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: immunomodulators, TLR modulators,HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBVantibodies targeting the surface antigens of the hepatitis B virus andbispecific antibodies and “antibody-like” therapeutic proteins (such asDARTs*, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, siRNA, miRNA gene therapyagents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV coreor capsid protein inhibitors).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with compoundssuch as those disclosed in U.S. Publication No. 2010/0143301 (GileadSciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S.Publication No. 2009/0047249 (Gilead Sciences), U.S. Pat. No. 8,722,054(Gilead Sciences), U.S. Publication No. 2014/0045849 (Janssen), U.S.Publication No. 2014/0073642 (Janssen), WO2014/056953 (Janssen),WO2014/076221 (Janssen), WO2014/128189 (Janssen), U.S. Publication No.2014/0350031 (Janssen), WO2014/023813 (Janssen), U.S. Publication No.2008/0234251 (Array Biopharma), U.S. Publication No. 2008/0306050 (ArrayBiopharma), U.S. Publication No. 2010/0029585 (Ventirx Pharma), U.S.Publication No. 2011/0092485 (Ventirx Pharma), US2011/0118235 (VentirxPharma), U.S. Publication No. 2012/0082658 (Ventirx Pharma), U.S.Publication No. 2012/0219615 (Ventirx Pharma), U.S. Publication No.2014/0066432 (Ventirx Pharma), U.S. Publication No. 2014/0088085(Ventirx Pharma), U.S. Publication No. 2014/0275167 (NoviraTherapeutics), U.S. Publication No. 2013/0251673 (Novira Therapeutics),U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S. Publication No.2014/0030221 (Gilead Sciences), U.S. Publication No. 2013/0344030(Gilead Sciences), U.S. Publication No. 2013/0344029 (Gilead Sciences),US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014/0343032 (Roche), WO2014037480(Roche), U.S. Publication No. 2013/0267517 (Roche), WO2014131847(Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167(Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281(Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888(Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337(Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652(Novira), US20150259324 (Novira), US20150132258 (Novira), U.S. Pat. No.9,181,288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche),US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.),WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (FlexusBiosciences, Inc.), U.S. Publication No. 2014/0330015 (OnoPharmaceutical), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical),U.S. Publication No. 2013/0217880 (Ono pharmaceutical), WO2016057924(Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel), U.S. Pat. No. 9,186,337B2 (OryzonGenomics), and other drugs for treating HBV, and combinations thereof.

HIV Combination Therapy

In certain embodiments, a method for treating or preventing an HIVinfection in a human or animal having or at risk of having the infectionis provided, comprising administering to the human or animal atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HIV infection in a human or animalhaving or at risk of having the infection is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

In certain embodiments, the compounds disclosed herein are formulated asa tablet, which may optionally contain one or more other compoundsuseful for treating HIV. In certain embodiments, the tablet can containanother active ingredient for treating HIV, such as HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, pharmacokinetic enhancers, or anycombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In some embodiments, the additional therapeutic agent may be an anti-HIVagent. In some embodiments, the additional therapeutic agent is selectedfrom the group consisting of HIV combination drugs, HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, immunomodulators, immunotherapeutic agents, antibody-drugconjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zincfinger nucleases, homing nucleases, synthetic nucleases, TALENs), celltherapies (such as chimeric antigen receptor T-cell, CAR-T, andengineered T cell receptors, TCR-T), latency reversing agents, compoundsthat target the HIV capsid (including capsid inhibitors), immune-basedtherapies, phosphatidylinositol 3-kinase (PI3K) inhibitors,alpha-4/beta-7 antagonists, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors,IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators,protein disulfide isomerase inhibitors, complement C5a receptorantagonists, DNA methyltransferase inhibitor, HIV vif gene modulators,Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors,TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinasemodulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicinginhibitors, Rev protein inhibitors, integrin antagonists, nucleoproteininhibitors, splicing factor modulators, COMM domain containing protein 1modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAGprotein inhibitors, HIV POL protein inhibitors, Complement Factor Hmodulators, ubiquitin ligase inhibitors, deoxycytidine kinaseinhibitors, cyclin dependent kinase inhibitors, proprotein convertasePC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reversetranscriptase priming complex inhibitors, G6PD and NADH-oxidaseinhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines,and other HIV therapeutic agents, or any combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, or anycombinations thereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); BIKTARVY® (bictegravir, emtricitabine,tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate,emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; lamivudine and tenofovir disoproxil fumarate;tenofovir and lamivudine; tenofovir alafenamide and emtricitabine;tenofovir alafenamide hemifumarate and emtricitabine; tenofoviralafenamide hemifumarate, emtricitabine, and rilpivirine; tenofoviralafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir;COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®;abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavirand ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine);TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC);atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavirsulfate and ritonavir; darunavir and cobicistat; dolutegravir andrilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir,abacavir sulfate, and lamivudine; lamivudine, nevirapine, andzidovudine; raltegravir and lamivudine; doravirine, lamivudine, andtenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovirdisoproxil; dolutegravir+lamivudine, lamivudine+abacavir+zidovudine,lamivudine+abacavir, lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin;and APH-0812, or any combinations thereof.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine,ACC-007, AIC-292, KM-023, PC-1005, and VM-1500.

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine,phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148,MK-8504 and KP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives,integrase-LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217,NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173,NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232),anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptideC25P, TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs.

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176 andGSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, protein kinase C(PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors,ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide,and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitininhibitors such as largazole analogs, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621,AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9,TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107; interleukin-15/Fc fusion protein;normferon; peginterferon alfa-2a; peginterferon alfa-2b; recombinantinterleukin-15; RPI-MN; GS-9620; STING modulators; RIG-I modulators;NOD2 modulators; and IR-103.

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed inUS20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953(Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen),US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (ArrayBiopharma), US20080306050 (Array Biopharma), US20100029585 (VentirxPharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma),US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma),US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma),US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Pat. No. 9,670,205 (Gilead Sciences Inc.),US20160289229 (Gilead Sciences Inc.), U.S. patent application Ser. No.15/692,161 (Gilead Sciences Inc.), and U.S. patent application Ser. No.15/692,093 (Gilead Sciences Inc.)

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

Alpha-4 Beta-7 Antagonists

Examples of Integrin alpha-4/beta-7 antagonists include PTG-100,TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs*, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecificantibodies, anti-nef single domain antibodies, anti-Rev antibody,camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIVtherapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab,Immuglo, and MB-66.

Further examples include bavituximab, UB-421, C2F5, 2G12, C4E10,C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121,PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32,7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014 and VRC07.

Additional examples of HIV bispecific antibodies include MGD014.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines, DNA vaccines, CD4-derivedpeptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401),Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5(rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax,Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines,TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4,HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001,ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particlevaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C fusionvaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine,anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cellvaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIVvaccine (PIKA adjuvant), I i-key/IIC class II epitope hybrid peptidevaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVAvaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine,recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine,RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIVvaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 polypeptidevaccine, rAd5 gag-pol env A/B/C vaccine, DNA.HTI and MVA.HTI.

Additional HIV Therapeutic Agents

Examples of additional HIV therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

Examples of other drugs for treating HIV include acemannan, alisporivir,BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid,rHIV7-sh1-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy,BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43,HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205,PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452,TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

Gene Therapy and Cell Therapy

Gene therapy and cell therapy include the genetic modification tosilence a gene; genetic approaches to directly kill the infected cells;the infusion of immune cells designed to replace most of the patient'sown immune system to enhance the immune response to infected cells, oractivate the patient's own immune system to kill infected cells, or findand kill the infected cells; and genetic approaches to modify cellularactivity to further alter endogenous immune responsiveness against theinfection.

Examples of Dendritic Cell Therapy Include AGS-004.

Gene Editors

Examples of gene editing systems include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system.

Examples of HIV targeting CRISPR/Cas9 systems include EBT101.

CAR-T Cell Therapy

CAR-T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises an HIV antigen-binding domain. The HIV antigens include an HIVenvelope protein or a portion thereof, gp120 or a portion thereof, a CD4binding site on gp120, the CD4-induced binding site on gp120, N glycanon gp120, the V2 of gp120, and the membrane proximal region on gp41. Insome embodiments, the immune effector cell is a T cell or an NK cell. Insome embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or acombination thereof.

Examples of HIV CAR-T cell therapy include VC-CAR-T.

TCR-T Cell Therapy

TCR-T cell therapy includes T cells engineered to target HIV derivedpeptides present on the surface of virus-infected cells.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); BIKTARVY® (bictegravir, emtricitabine,tenofovir alafenamide); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofoviralafenamide hemifumarate, or bictegravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, andbictegravir and a second additional therapeutic agent selected from thegroup consisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, tenofovir alafenamide hemifumarate, andbictegravir and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine.

A compound as disclosed herein may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound(e.g., from 1 mg to 500 mg of compound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30,or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of Formula I, II, IIa,III, IV, or V) may be combined with the agents provided herein in anydosage amount of the compound (e.g., from 1 mg to 500 mg of compound) asif each combination of dosages were specifically and individuallylisted.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of Formula I, II, IIa, III, IV, or V) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 1 mg to 500 mg of compound) as if each combinationof dosages were specifically and individually listed.

Cancer and/or Hyper-Proliferative Disease Combination Therapy

In one embodiment, the compound provided herein may be employed withother therapeutic methods of cancer treatment. Preferably, combinationtherapy with chemotherapeutic, hormonal, antibody, surgical and/orradiation treatments are contemplated.

In some embodiments, the further anti-cancer therapy is surgery and/orradiotherapy. In some embodiments, the further anti-cancer therapy is atleast one additional cancer medicament.

In some embodiments, there is provided a combination comprising acompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof and at least one further cancer medicament.

In some embodiments, there is provided a combination comprising acompound of Formula I, II, IIa, III, IV, or V, or a pharmaceuticallyacceptable salt thereof and at least one further cancer medicament, foruse in therapy.

In some embodiments, there is provided the use of a combinationcomprising a compound of Formula I, II, IIa, III, IV, or V, or apharmaceutically acceptable salt thereof and at least one cancermedicament, in the manufacture of a medicament for the treatment ofcancer.

Examples of further cancer medicaments include intercalating substancessuch as anthracycline, doxorubicin, idarubicin, epirubicin, anddaunorubicin; topoisomerase inhibitors such as irinotecan, topotecan,camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone,amsacrine, ellipticines and aurintricarboxylic acid; nitrosoureacompounds such as carmustine (BCNU), lomustine (CCNU), and streptozocin;nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine,bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamid andifosfamide; alkyl sulfonates such as busulfan and treosulfan; alkylatingagents such as procarbazin, dacarbazin, temozolomid and thiotepa;platinum analogues such as cisplatin, carboplatin, nedaplatin,oxaliplatin, satraplatin, and triplatin tetranitrate; microtubuledisruptive drugs such as vinblastine, colcemid and nocodazole;antifolates like methotrexate, aminopterin, dichloromethotrexat,pemetrexed, raltitrexed and pralatrexate: purine analogues likeazathioprine, mercaptopurine, thioguanine, fludarabine, fludarabinephosphate, pentostatin and cladribine; pyrimidine analogues like5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine;steroids such as gestagene, androgene, glucocorticoids, dexamethasone,prednisolone, and prednisone; anti-cancer antibodies such as monoclonalantibodies, e.g., alemtuzumab, apolizumab, cetuximab, epratuzumab,galiximab, gemtuzumab, ipilimumab, labetuzumab, panitumumab, rituximab,trastuzumab, nimotuzumab, mapatumumab, matuzumab, rhMab ICR62 andpertuzumab, radioactively labeled antibodies and antibody-drugconjugates; anti-cancer peptides such as radioactively labeled peptidesand peptide-drug conjugates; and taxane and taxane analogues such aspaclitaxel and docetaxel.

In certain embodiments, a method for treating or preventing a cancer orhyper-proliferative disease in a human or animal having or at risk ofhaving the cancer or hyper-proliferative disease is provided, comprisingadministering to the human or animal a therapeutically effective amountof a compound of Formula I, II, IIa, III, IV, or V as disclosed herein,or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating a cancer or hyper-proliferativedisease in a human or animal having or at risk of having the cancer orhyper-proliferative disease is provided, comprising administering to thehuman or animal a therapeutically effective amount of a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating a cancer or hyper-proliferative disease, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound disclosed herein, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofone or more additional therapeutic agents which are suitable fortreating cancer or hyper-proliferative disease.

The compounds described herein may be used or combined with one or moreof a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenicagent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeuticantibody, a bispecific antibody and “antibody-like” therapeutic protein(such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives),an antibody-drug conjugate (ADC), a radiotherapeutic agent, ananti-neoplastic agent, an anti-proliferation agent, an oncolytic virus,a gene modifier or editor (such as CRISPR/Cas9, zinc finger nucleases orsynthetic nucleases, TALENs), a CAR (chimeric antigen receptor) T-cellimmunotherapeutic agent, an engineered T cell receptor (TCR-T), or anycombination thereof. These therapeutic agents may be in the forms ofcompounds, antibodies, polypeptides, or polynucleotides. In oneembodiment, provided herein is a product comprising a compound describedherein and an additional therapeutic agent as a combined preparation forsimultaneous, separate, or sequential use in therapy.

The one or more additional therapeutic agents include, but are notlimited to, an inhibitor, agonist, antagonist, ligand, modulator,stimulator, blocker, activator or suppressor of a gene, ligand,receptor, protein, or factor. Non-limiting examples of additionaltherapeutic agents include:

-   -   Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such        as ABL1), Acetyl-CoA carboxylase (such as ACC1/2), activated CDC        kinase (ACK, such as ACK1), Adenosine deaminase, adenosine        receptor (such as A2B, A2a, A3), Adenylate cyclase, ADP ribosyl        cyclase-1, adrenocorticotropic hormone receptor (ACTH),        Aerolysin, AKT1 gene, Alk-5 protein kinase, Alkaline        phosphatase, Alpha 1 adrenoceptor, Alpha 2 adrenoceptor,        Alpha-ketoglutarate dehydrogenase (KGDH), Aminopeptidase N, AMP        activated protein kinase, anaplastic lymphoma kinase (ALK, such        as ALK1), Androgen receptor, Angiopoietin (such as ligand-1,        ligand-2), Angiotensinogen (AGT) gene, murine thymoma viral        oncogene homolog 1 (AKT) protein kinase (such as AKT1, AKT2,        AKT3), apolipoprotein A-I (APOA1) gene, Apoptosis inducing        factor, apoptosis protein (such as 1, 2), apoptosis        signal-regulating kinase (ASK, such as ASK1), Arginase (I),        Arginine deiminase, Aromatase, Asteroid homolog 1 (ASTE1) gene,        ataxia telangiectasia and Rad 3 related (ATR) serine/threonine        protein kinase, Aurora protein kinase (such as 1, 2), Ax1        tyrosine kinase receptor, Baculoviral IAP repeat containing 5        (BIRC5) gene, Basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2        binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint        cluster region) protein and gene, Beta adrenoceptor,        Beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen        CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte        stimulator ligand, Bone morphogenetic protein-10 ligand, Bone        morphogenetic protein-9 ligand modulator, Brachyury protein,        Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl        tyrosine kinase, Bromodomain and external domain (BET)        bromodomain containing protein (such as BRD2, BRD3, BRD4),        Bruton's tyrosine kinase (BTK), Calmodulin, calmodulin-dependent        protein kinase (CaMK, such as CAMKII), Cancer testis antigen 2,        Cancer testis antigen NY-ESO-1, cancer/testis antigen 1B (CTAG1)        gene, Cannabinoid receptor (such as CB1, CB2), Carbonic        anhydrase, casein kinase (CK, such as CKI, CKII), Caspase (such        as caspase-3, caspase-7, Caspase-9), caspase 8 apoptosis-related        cysteine peptidase CASP8-FADD-like regulator, Caspase        recruitment domain protein-15, Cathepsin G, CCR5 gene,        CDK-activating kinase (CAK), Checkpoint kinase (such as        CHK1,CHK2), chemokine (C-C motif) receptor (such as CCR2, CCR4,        CCR5), chemokine (C-X-C motif) receptor (such as CXCR4, CXCR1        and CXCR2), Chemokine CC21 ligand, Cholecystokinin CCK2        receptor, Chorionic gonadotropin, c-Kit (tyrosine-protein kinase        Kit or CD 117), Claudin (such as 6, 18), cluster of        differentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37,        CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44,        CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene,        CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122,        CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276        antigen; clusterin (CLU) gene, Clusterin, c-Met (hepatocyte        growth factor receptor (HGFR)), Complement C3, Connective tissue        growth factor, COP9 signalosome subunit 5, CSF-1        (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4        (cytotoxic T-lymphocyte protein 4) receptor, Cyclin D1, Cyclin        G1, cyclin-dependent kinases (CDK, such as CDK1, CDK1B, CDK2-9),        cyclooxygenase (such as 1, 2), CYP2B1 gene, Cysteine        palmitoyltransferase porcupine, Cytochrome P450 11B2, Cytochrome        P450 17, cytochrome P450 17A1, Cytochrome P450 2D6, cytochrome        P450 3A4, Cytochrome P450 reductase, cytokine signalling-1,        cytokine signalling-3, Cytoplasmic isocitrate dehydrogenase,        Cytosine deaminase, cytosine DNA methyltransferase, cytotoxic        T-lymphocyte protein-4, DDR2 gene, Delta-like protein ligand        (such as 3, 4), Deoxyribonuclease, Dickkopf-1 ligand,        dihydrofolate reductase (DHFR), Dihydropyrimidine dehydrogenase,        Dipeptidyl peptidase IV, discoidin domain receptor (DDR, such as        DDR1), DNA binding protein (such as HU-beta), DNA dependent        protein kinase, DNA gyrase, DNA methyltransferase, DNA        polymerase (such as alpha), DNA primase, dUTP pyrophosphatase,        L-dopachrome tautomerase, echinoderm microtubule like protein 4,        EGFR tyrosine kinase receptor, Elastase, Elongation factor 1        alpha 2, Elongation factor 2, Endoglin, Endonuclease,        Endoplasmin, Endosialin, Endostatin, endothelin (such as ET-A,        ET-B), Enhancer of zeste homolog 2 (EZH2), Ephrin (EPH) tyrosine        kinase (such as Epha3, Ephb4), Ephrin B2 ligand, epidermal        growth factor, epidermal growth factor receptors (EGFR),        epidermal growth factor receptor (EGFR) gene, Epigen, Epithelial        cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian        erythroblastic leukemia viral oncogene homolog 2) tyrosine        kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4        tyrosine kinase receptor, E-selectin, Estradiol 17 beta        dehydrogenase, Estrogen receptor (such as alpha, beta), Estrogen        related receptor, Eukaryotic translation initiation factor 5A        (EIF5A) gene, Exportin 1, Extracellular signal related kinase        (such as 1, 2), Extracellular signal-regulated kinases (ERK),        Factor (such as Xa, VIIa), farnesoid x receptor (FXR), Fas        ligand, Fatty acid synthase (FASN), Ferritin, FGF-2 ligand,        FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2,        FGF4), Fibronectin, Fms-related tyrosine kinase 3 (Flt3), focal        adhesion kinase (FAK, such as FAK2), folate hydrolase        prostate-specific membrane antigen 1 (FOLH1), Folate receptor        (such as alpha), Folate, Folate transporter 1, FYN tyrosine        kinase, paired basic amino acid cleaving enzyme (FURIN),        Beta-glucuronidase, Galactosyltransferase, Galectin-3,        Ganglioside GD2, Glucocorticoid, glucocorticoid-induced        TNFR-related protein GITR receptor, Glutamate carboxypeptidase        II, glutaminase, Glutathione S-transferase P, glycogen synthase        kinase (GSK, such as 3-beta), Glypican 3 (GPC3),        gonadotropin-releasing hormone (GNRH), Granulocyte macrophage        colony stimulating factor (GM-CSF) receptor, Granulocyte-colony        stimulating factor (GCSF) ligand, growth factor receptor-bound        protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein)        calcium binding protein, molecular chaperone groEL2 gene, Heat        shock protein (such as 27, 70, 90 alpha, beta), Heat shock        protein gene, Heat stable enterotoxin receptor, Hedgehog        protein, Heparanase, Hepatocyte growth factor, HERV-H LTR        associating protein 2, Hexose kinase, Histamine H2 receptor,        Histone methyltransferase (DOT1L), histone deacetylase (HDAC,        such as 1, 2, 3, 6, 10, 11), Histone H1, Histone H3, HLA class I        antigen (A-2 alpha), HLA class II antigen, Homeobox protein        NANOG, HSPB1 gene, Human leukocyte antigen (HLA), Human        papillomavirus (such as E6, E7) protein, Hyaluronic acid,        Hyaluronidase, Hypoxia inducible factor-1 alpha (HIF1α),        Imprinted Maternally Expressed Transcript (H19) gene,        mitogen-activated protein kinase kinase kinase kinase 1        (MAP4K1), tyrosine-protein kinase HCK, I-Kappa-B kinase (IKK,        such as IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15,        IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3        receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (such as G, G1,        G2, K, M), Immunoglobulin Fc receptor, Immunoglobulin gamma Fc        receptor (such as I, III, IIIA), indoleamine 2,3-dioxygenase        (IDO, such as IDO1), indoleamine pyrrole 2,3-dioxygenase 1        inhibitor, insulin receptor, Insulin-like growth factor (such as        1, 2), Integrin alpha-4/beta-1, integrin alpha-4/beta-7,        Integrin alpha-5/beta-1, Integrin alpha-V/beta-3, Integrin        alpha-V/beta-5, Integrin alpha-V/beta-6, Intercellular adhesion        molecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta,        gamma), Interferon inducible protein absent in melanoma 2        (AIM2), interferon type I receptor, Interleukin 1 ligand,        Interleukin 13 receptor alpha 2, interleukin 2 ligand,        interleukin-1 receptor-associated kinase 4 (IRAK4),        Interleukin-2, Interleukin-29 ligand, isocitrate dehydrogenase        (such as IDH1, IDH2), Janus kinase (JAK, such as JAK1, JAK2),        Jun N terminal kinase, kallikrein-related peptidase 3 (KLK3)        gene, Killer cell Ig like receptor, Kinase insert domain        receptor (KDR), Kinesin-like protein KIF11, Kirsten rat sarcoma        viral oncogene homolog (KRAS) gene, Kisspeptin (KiSS-1)        receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral        oncogene homolog (KIT) tyrosine kinase, lactoferrin,        Lanosterol-14 demethylase, LDL receptor related protein-1,        Leukotriene A4 hydrolase, Listeriolysin, L-Selectin, Luteinizing        hormone receptor, Lyase, lymphocyte activation gene 3 protein        (LAG-3), Lymphocyte antigen 75, Lymphocyte function antigen-3        receptor, lymphocyte-specific protein tyrosine kinase (LCK),        Lymphotactin, Lyn (Lck/Yes novel) tyrosine kinase, lysine        demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D),        Lysophosphatidate-1 receptor, lysosomal-associated membrane        protein family (LAMP) gene, Lysyl oxidase homolog 2, lysyl        oxidase protein (LOX), lysyl oxidase-like protein (LOXL, such as        LOXL2), Hematopoietic Progenitor Kinase 1 (HPK1), Hepatocyte        growth factor receptor (MET) gene, macrophage colony-stimulating        factor (MCSF) ligand, Macrophage migration inhibitory fact,        MAGEC1 gene, MAGEC2 gene, Major vault protein, MAPK-activated        protein kinase (such as MK2), Mas-related G-protein coupled        receptor, matrix metalloprotease (MMP, such as MMP2, MMP9),        Mcl-1 differentiation protein, Mdm2 p53-binding protein, Mdm4        protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein        Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen        family A3 (MAGEA3) gene, Melanoma associated antigen (such as 1,        2,3,6), Membrane copper amine oxidase, Mesothelin, MET tyrosine        kinase, Metabotropic glutamate receptor 1, Metalloreductase        STEAP1 (six transmembrane epithelial antigen of the prostate 1),        Metastin, methionine aminopeptidase-2, Methyltransferase,        Mitochondrial 3 ketoacyl CoA thiolase, mitogen-activate protein        kinase (MAPK), mitogen-activated protein kinase (MEK, such as        MEK1, MEK2), mTOR (mechanistic target of rapamycin)        (serine/threonine kinase), mTOR complex (such as 1,2), mucin        (such as 1, 5A, 16), mut T homolog (MTH, such as MTH1), Myc        proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene,        myristoylated alanine-rich protein kinase C substrate (MARCKS)        protein, NAD ADP ribosyltransferase, natriuretic peptide        receptor C, Neural cell adhesion molecule 1, Neurokinin 1 (NK1)        receptor, Neurokinin receptor, Neuropilin 2, NF kappa B        activating protein, NIMA-related kinase 9 (NEK9), Nitric oxide        synthase, NK cell receptor, NK3 receptor, NKG2 A B activating NK        receptor, Noradrenaline transporter, Notch (such as Notch-2        receptor, Notch-3 receptor, Notch-4 receptor), Nuclear erythroid        2-related factor 2, Nuclear Factor (NF) kappa B, Nucleolin,        Nucleophosmin, nucleophosmin-anaplastic lymphoma kinase        (NPM-ALK), 2 oxoglutarate dehydrogenase, 2,5-oligoadenylate        synthetase, O-methylguanine DNA methyltransferase, Opioid        receptor (such as delta), Ornithine decarboxylase, Orotate        phosphoribosyltransferase, orphan nuclear hormone receptor        NR4A1, Osteocalcin, Osteoclast differentiation factor,        Osteopontin, OX-40 (tumor necrosis factor receptor superfamily        member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase,        p38 MAP kinase, p53 tumor suppressor protein, Parathyroid        hormone ligand, peroxisome proliferator-activated receptors        (PPAR, such as alpha, delta, gamma), P-Glycoprotein (such as 1),        phosphatase and tensin homolog (PTEN), phosphatidylinositol        3-kinase (PI3K), phosphoinositide-3 kinase (PI3K such as alpha,        delta, gamma), phosphorylase kinase (PK), PKN3 gene, placenta        growth factor, platelet-derived growth factor (PDGF, such as        alpha, beta), Platelet-derived growth factor (PDGF, such as        alpha, beta), Pleiotropic drug resistance transporter, Plexin        B1, PLK1 gene, polo-like kinase (PLK), Polo-like kinase 1, Poly        ADP ribose polymerase (PARP, such as PARP1, 2 and 3),        Preferentially expressed antigen in melanoma (PRAME) gene,        Prenyl-binding protein (PrPB), Probable transcription factor        PML, Progesterone receptor, Programmed cell death 1 (PD-1),        Programmed cell death ligand 1 inhibitor (PD-L1), Prosaposin        (PSAP) gene, Prostanoid receptor (EP4), prostate specific        antigen, Prostatic acid phosphatase, proteasome, Protein E7,        Protein farnesyltransferase, protein kinase (PK, such as A, B,        C), protein tyrosine kinase, Protein tyrosine phosphatase beta,        Proto-oncogene serine/threonine-protein kinase (PIM, such as        PIM-1, PIM-2, PIM-3), P-Selectin, Purine nucleoside        phosphorylase, purinergic receptor P2X ligand gated ion channel        7 (P2X7), Pyruvate dehydrogenase (PDH), Pyruvate dehydrogenase        kinase, Pyruvate kinase (PYK), 5-Alpha-reductase, Raf protein        kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RET        gene, Ret tyrosine kinase receptor, retinoblastoma associated        protein, retinoic acid receptor (such as gamma), Retinoid X        receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras        homolog) associated protein kinase 2, ribonuclease,        Ribonucleotide reductase (such as M2 subunit), Ribosomal protein        S6 kinase, RNA polymerase (such as I, II), Ron (Recepteur        d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene 1,        receptor tyrosine kinase) gene, Ros1 tyrosine kinase,        Runt-related transcription factor 3, Gamma-secretase, S100        calcium binding protein A9, Sarco endoplasmic calcium ATPase,        Second mitochondria-derived activator of caspases (SMAC)        protein, Secreted frizzled related protein-2, Semaphorin-4D,        Serine protease, serine/threonine kinase (STK),        serine/threonine-protein kinase (TBK, such as TBK1), signal        transduction and transcription (STAT, such as STAT-1, STAT-3,        STAT-5), Signaling lymphocytic activation molecule (SLAM) family        member 7, six-transmembrane epithelial antigen of the prostate        (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor,        Sodium iodide cotransporter, Sodium phosphate cotransporter 2B,        Somatostatin receptor (such as 1, 2, 3, 4, 5), Sonic hedgehog        protein, Son of sevenless (SOS), Specific protein 1 (Sp1)        transcription factor, Sphingomyelin synthase, Sphingosine kinase        (such as 1, 2), Sphingosine-1-phosphate receptor-1, spleen        tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, STAT3        gene, Steroid sulfatase, Stimulator of interferon genes (STING)        receptor, stimulator of interferon genes protein, Stromal        cell-derived factor 1 ligand, SUMO (small ubiquitin-like        modifier), Superoxide dismutase, Survivin protein, Synapsin 3,        Syndecan-1, Synuclein alpha, T cell surface glycoprotein CD28,        tank-binding kinase (TBK), TATA box-binding protein-associated        factor RNA polymerase I subunit B (TAF1B) gene, T-cell CD3        glycoprotein zeta chain, T-cell differentiation antigen CD6,        T-cell immunoglobulin and mucin-domain containing-3 (TIM-3),        T-cell surface glycoprotein CD8, Tec protein tyrosine kinase,        Tek tyrosine kinase receptor, telomerase, Telomerase reverse        transcriptase (TERT) gene, Tenascin, TGF beta 2 ligand,        Thrombopoietin receptor, Thymidine kinase, Thymidine        phosphorylase, Thymidylate synthase, Thymosin (such as alpha 1),        Thyroid hormone receptor, Thyroid stimulating hormone receptor,        Tissue factor, TNF related apoptosis inducing ligand, TNFR1        associated death domain protein, TNF-related apoptosis-inducing        ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like        receptor (TLR such as 1-13), topoisomerase (such as I, II, III),        Transcription factor, Transferase, Transferrin, Transforming        growth factor (TGF, such as beta) kinase, Transforming growth        factor TGF-β receptor kinase, Transglutaminase, Translocation        associated protein, Transmembrane glycoprotein NMB, Trop-2        calcium signal transducer, trophoblast glycoprotein (TPBG) gene,        Trophoblast glycoprotein, Tropomyosin receptor kinase (Trk)        receptor (such as TrkA, TrkB, TrkC), Tryptophan 5-hydroxylase,        Tubulin, Tumor necrosis factor (TNF, such as alpha, beta), Tumor        necrosis factor 13C receptor, tumor progression locus 2 (TPL2),        Tumor protein 53 (TP53) gene, Tumor suppressor candidate 2        (TUSC2) gene, Tyrosinase, Tyrosine hydroxylase, tyrosine kinase        (TK), Tyrosine kinase receptor, Tyrosine kinase with        immunoglobulin-like and EGF-like domains (TIE) receptor,        Tyrosine protein kinase ABL1 inhibitor, Ubiquitin, Ubiquitin        carboxyl hydrolase isozyme L5, Ubiquitin thioesterase-14,        Ubiquitin-conjugating enzyme E21 (UBE2I, UBC9), Urease,        Urokinase plasminogen activator, Uteroglobin, Vanilloid VR1,        Vascular cell adhesion protein 1, vascular endothelial growth        factor receptor (VEGFR), V-domain Ig suppressor of T-cell        activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3        receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3 receptor,        Proto-oncogene tyrosine-protein kinase Yes, Wee-1 protein        kinase, Wilms' tumor antigen 1, Wilms' tumor protein, X-linked        inhibitor of apoptosis protein, Zinc finger protein        transcription factor, or any combinations thereof.

Non-limiting examples of additional therapeutic agents may becategorized by their mechanism of action into, for example, thefollowing groups:

-   -   anti-metabolites/anti-cancer agents, such as pyrimidine analogs        floxuridine, capecitabine, cytarabine, CPX-351 (liposomal        cytarabine, daunorubicin), and TAS-118;    -   purine analogs, folate antagonists (such as pralatrexate), and        related inhibitors;    -   antiproliferative/antimitotic agents including natural products,        such as vinca alkaloids (vinblastine, vincristine) and        microtubule disruptors such as taxane (paclitaxel, docetaxel),        vinblastin, nocodazole, epothilones, vinorelbine (NAVELBINE®),        and epipodophyllotoxins (etoposide, teniposide);    -   DNA damaging agents, such as actinomycin, amsacrine, busulfan,        carboplatin, chlorambucil, cisplatin, cyclophosphamide        (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin,        iphosphamide, melphalan, merchlorethamine, mitomycin C,        mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere,        teniposide, etoposide, and triethylenethiophosphoramide;    -   DNA-hypomethylating agents, such as guadecitabine (SGI-110) and        ASTX727;    -   antibiotics such as dactinomycin, daunorubicin, doxorubicin,        idarubicin, anthracyclines, mitoxantrone, bleomycins, and        plicamycin (mithramycin);    -   enzymes such as L-asparaginase which systemically metabolizes        L-asparagine and deprives cells which do not have the capacity        to synthesize their own asparagine;    -   antiplatelet agents;    -   DNAi oligonucleotides targeting Bcl-2, such as PNT2258;    -   agents that activate or reactivate latent human immunodeficiency        virus (HIV), such as panobinostat and romidepsin;    -   asparaginase stimulators, such as crisantaspase (Erwinase®) and        GRASPA (ERY-001, ERY-ASP), and calaspargase pegol;    -   pan-Trk, ROS1 and ALK inhibitors, such as entrectinib and        TPX-0005;    -   anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib        and ceritinib;    -   antiproliferative/antimitotic alkylating agents, such as        nitrogen mustard cyclophosphamide and analogs (melphalan,        chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas        (carmustine) and analogs, streptozocin, and triazenes        (dacarbazine);    -   antiproliferative/antimitotic antimetabolites, such as folic        acid analogs (methotrexate);    -   platinum coordination complexes (cisplatin, oxiloplatinim, and        carboplatin), procarbazine, hydroxyurea, mitotane, and        aminoglutethimide;    -   hormones, hormone analogs (estrogen, tamoxifen, goserelin,        bicalutamide, and nilutamide), and aromatase inhibitors        (letrozole and anastrozole);    -   anticoagulants such as heparin, synthetic heparin salts, and        other inhibitors of thrombin;    -   fibrinolytic agents such as tissue plasminogen activator,        streptokinase, urokinase, aspirin, dipyridamole, ticlopidine,        and clopidogrel;    -   antimigratory agents;    -   antisecretory agents (breveldin);    -   immunosuppressives, such as tacrolimus, sirolimus, azathioprine,        and mycophenolate;    -   growth factor inhibitors, and vascular endothelial growth factor        inhibitors;    -   fibroblast growth factor inhibitors, such as FPA14;    -   anti-VEGFR antibodies, such as IMC-3C5, GNR-011 and tanibirumab;    -   anti-VEGF/DDL4 antibodies, such as ABT-165;    -   anti-cadherins antibodies, such as HKT-288;    -   anti-CD70 antibodies, such as AMG-172; anti-leucine-rich repeat        containing 15 (LRRC15) antibodies, such as ABBV-085 and        ARGX-110;    -   angiotensin receptor blockers and nitric oxide donors;    -   antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx,        EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), and        IONIS-STAT3-2.5Rx;    -   DNA interference oligonucleotides, such as PNT2258 and AZD-9150;    -   anti-ANG-2 antibodies, such as MEDI3617, and LY3127804;    -   anti-ANG-1/ANG-2 antibodies, such as AMG-780;    -   anti-MET/EGFR antibodies, such as LY3164530;    -   anti-EGFR antibodies, such as ABT-414, AMG-595, necitumumab,        ABBV-221, depatuxizumab mafodotin (ABT-414), tomuzotuximab,        ABT-806, vectibix, modotuximab, and RM-1929;    -   anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820,        and FPA-008 (cabiralizumab);    -   anti-CD40 antibodies, such as RG7876, SEA-CD40, APX-005M, and        ABBV-428;    -   anti-endoglin antibodies, such as TRC105 (carotuximab);    -   anti-CD45 antibodies, such as 131I-BC8 (lomab-B);    -   anti-HER3 antibodies, such as LJM716, and GSK2849330;    -   anti-HER2 antibodies, such as margetuximab, MEDI4276, and        BAT-8001;    -   anti-HLA-DR antibodies, such as IMMU-114;    -   anti-TL-3 antibodies, such as JNJ-56022473;    -   anti-OX40 antibodies, such as MEDI6469, MEDI6383, MEDI0562        (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998,        INCAGN1949, BMS-986178, GBR-8383, and ABBV-368;    -   anti-EphA3 antibodies, such as KB-004;    -   anti-CD20 antibodies, such as obinutuzumab, IGN-002;    -   anti-CD20/CD3 antibodies, such as RG7828;    -   anti-CD37 antibodies, such as AGS67E, and otlertuzumab        (TRU-016);    -   anti-ENPP3 antibodies, such as AGS-16C3F;    -   anti-FGFR-3 antibodies, such as LY3076226, and B-701;    -   anti-FGFR-2 antibodies, such as GAL-F2;    -   anti-C5 antibodies, such as ALXN-1210;    -   anti-CD27 antibodies, such as varlilumab (CDX-1127);    -   anti-TROP-2 antibodies, such as IMMU-132    -   anti-NKG2a antibodies, such as monalizumab;    -   anti-VISTA antibodies, such as H11BD-002;    -   anti-PVRIG antibodies, such as COM-701;    -   anti-EpCAM antibodies, such as VB4-845;    -   anti-BCMA antibodies, such as GSK-2857916    -   anti-CEA antibodies, such as RG-7813;    -   anti-cluster of differentiation 3 (CD3) antibodies, such as        MGD015;    -   anti-folate receptor alpha antibodies, such as IMGN853;    -   MCL-1 inhibitors, such as AMG-176, S-64315, AZD-5991, 483-LM,        A-1210477, UMI-77, and JKY-5-037;    -   epha2 inhibitors, such as MM-310;    -   anti LAG-3 antibodies, such as relatlimab (ONO-4482), LAG-525,        MK-4280, and REGN-3767;    -   raf kinase/VEGFR inhibitors, such as RAF-265;    -   polycomb protein (EED) inhibitors, such as MAK683;    -   anti-fibroblast activation protein (FAP)/TL-2R antibodies, such        as RG7461;    -   anti-fibroblast activation protein (FAP)/TRATL-R2 antibodies,        such as RG7386;    -   anti-fucosyl-GM1 antibodies, such as BMS-986012;    -   p38 MAP kinase inhibitors, such as ralimetinib;    -   PRMT1 inhibitors, such as MS203;    -   Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;    -   FLT3-ITD inhibitors, such as BCI-332;    -   Nuclear erythroid 2-related factor 2 stimulators, such as        omaveloxolone (RTA-408);    -   Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195,        and ONO-7579;    -   anti-ICOS antibodies, such as JTX-2011, and GSK3359609;    -   anti-DR5 (TRATL2) antibodies, such as DS-8273;    -   anti-GD2 antibodies, such as APN-301;    -   anti-interleukin-17 (IL-17) antibodies, such as CJM-112;    -   anti-carbonic anhydrase IX antibodies, such as TX-250;    -   anti-CD38-attenukine, such as TAK573;    -   anti-Mucin 1 antibodies, such as gatipotuzumab;    -   Mucin 1 inhibitors, such as GO-203-2C;    -   MARCKS protein inhibitors, such as BIO-11006;    -   Folate antagonists, such as arfolitixorin;    -   Galectin-3 inhibitors, such as GR-MD-02;    -   Phosphorylated P68 inhibitors, such as RX-5902;    -   CD95/TNF modulators, such as ofranergene obadenovec;    -   PI3K/Akt/mTOR inhibitors, such as ABTL-0812;    -   pan-PIM kinase inhibitors, such as INCB-053914;    -   IL-12 gene stimulators, such as EGEN-001, and tavokinogene        telseplasmid;    -   Heat shock protein HSP90 inhibitors, such as TAS-116, and        PEN-866;    -   VEGF/HGF antagonists, such as MP-0250;    -   SYK tyrosine kinase/FLT3 tyrosine kinase inhibitors, such as        TAK-659;    -   SYK tyrosine kinase/JAK tyrosine kinase inhibitors, such as        ASN-002;    -   FLT3 tyrosine kinase inhibitor, such as FF-10101;    -   FLT3 tyrosine kinase agonist, such as CDX-301;    -   FLT3/MEK1 inhibitors, such as E-6201;    -   IL-24 antagonist, such as AD-IL24;    -   RIG-I agonists, such as RGT-100;    -   Aerolysin stimulators, such as topsalysin;    -   P-Glycoprotein 1 inhibitors, such as HM-30181A;    -   CSF-1 antagonists, such as ARRY-382, and BLZ-945;    -   anti-Mesothelin antibodies, such as SEL-403;    -   Thymidine kinase stimulators, such as aglatimagene besadenovec;    -   Polo-like kinase 1 inhibitors, such as PCM-075;    -   TLR-7 agonists, such as TMX-101 (imiquimod);    -   NEDD8 inhibitors, such as pevonedistat (MLN-4924), and TAS-4464;    -   Pleiotropic pathway modulators, such as avadomide (CC-122);    -   FoxM1 inhibitors, such as thiostrepton;    -   Anti-MUC1 antibodies, such as Mab-AR-20.5;    -   anti-CD38 antibodies, such as isatuximab, and MOR-202;    -   UBA1 inhibitors, such as TAK-243;    -   Src tyrosine kinase inhibitors, such as VAL-201;    -   VDAC/HK inhibitors, such as VDA-1102;    -   BRAF/PI3K inhibitors, such as ASN-003;    -   Elf4a inhibitors, such as rohinitib, eFT226;    -   TP53 gene stimulators, such as ad-p53;    -   PD-L1/EGFR inhibitors, such as GNS-1480;    -   Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;    -   SIRT3 inhibitors, such as YC8-02;    -   Stromal cell-derived factor 1 ligand inhibitors, such as        olaptesed pegol (NOX-A12);    -   IL-4 receptor modulators, such as MDNA-55;    -   Arginase-I stimulators, such as pegzilarginase;    -   Topoisomerase I inhibitor/hypoxia inducible factor-1 alpha        inhibitors, such as PEG-SN38 (firtecan pegol);    -   Hypoxia inducible factor-1 alpha inhibitors, such as PT-2977,        and PT-2385;    -   CD122 agonists such as NKTR-214;    -   p53 tumor suppressor protein stimulators such as kevetrin;    -   Mdm4/Mdm2 p53-binding protein inhibitors, such as ALRN-6924;    -   kinesin spindle protein (KSP) inhibitors, such as filanesib        (ARRY-520);    -   CD80-fc fusion protein inhibitors, such as FPT-155;    -   Menin and mixed lineage leukemia (MLL) inhibitors such as        KO-539;    -   Liver x receptor agonists, such as RGX-104;    -   IL-10 agonists, such as AM-0010;    -   EGFR/ErbB-2 inhibitors, such as varlitinib;    -   VEGFR/PDGFR inhibitors, such as vorolanib;    -   IRAK4 inhibitors, such as CA-4948;    -   anti-TLR-2 antibodies, such as OPN-305;    -   Calmodulin modulators, such as CBP-501;    -   Glucocorticoid receptor antagonists, such as relacorilant        (CORT-125134);    -   Second mitochondria-derived activator of caspases (SMAC) protein        inhibitors, such as BI-891065;    -   Lactoferrin modulators, such as LTX-315;    -   Kit tyrosine kinase/PDGF receptor alpha antagonists such as        DCC-2618;    -   KIT inhibitors, such as PLX-9486;    -   Exportin 1 inhibitors, such as eltanexor;    -   EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;    -   anti-CD33 antibodies, such as IMGN-779;    -   anti-KMA antibodies, such as MDX-1097;    -   anti-TIM-3 antibodies, such as TSR-022, LY-3321367, and MBG-453;    -   anti-CD55 antibodies, such as PAT-SC1;    -   anti-PSMA antibodies, such as ATL-101;    -   anti-CD100 antibodies, such as VX-15;    -   anti-EPHA3 antibodies, such as fibatuzumab;    -   anti-Erbb antibodies, such as CDX-3379, HLX-02, and        seribantumab;    -   anti-APRIL antibodies, such as BION-1301;    -   Anti-Tigit antidbodies, such as BMS-986207, and RG-6058;    -   CHST15 gene inhibitors, such as STNM-01;    -   RAS inhibitors, such as NEO-100;    -   Somatostatin receptor antagonist, such as OPS-201;    -   CEBPA gene stimulators, such as MTL-501;    -   DKK3 gene modulators, such as MTG-201;    -   p70s6k inhibitors, such as MSC2363318A;    -   methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891,        and APL-1202;    -   arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;    -   anti-programmed cell death protein 1 (anti-PD-1) antibodies,        such as nivolumab (OPDIVO®, BMS-936558, MDX-1 106),        pembrolizumab (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab,        CAS Reg. No. 1374853-91-4), pidilizumab, PF-06801591, BGB-A317,        GLS-010 (WBP-3055), AK-103 (HX-008), MGA-012, BI-754091,        REGN-2810 (cemiplimab), AGEN-2034, JS-001, JNJ-63723283,        genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201,        BAT-1306, and anti-programmed death-ligand 1 (anti-PD-L1)        antibodies such as BMS-936559, atezolizumab (MPDL3280A),        durvalumab (MEDI4736), avelumab, CK-301, (MSB0010718C),        MEDI0680, CX-072, CBT-502, PDR-001 (spartalizumab), TSR-042        (dostarlimab), JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155,        KN-035, IBI-308, FAZ-053, and MDX1105-01;    -   PD-L1/VISTA antagonists such as CA-170;    -   anti-PD-L1/TGFβ antibodies, such as M7824;    -   anti-transferrin antibodies, such as CX-2029;    -   anti-IL-8 (Interleukin-8) antibodies, such as HuMax-Inflam;    -   ATM (ataxia telangiectasia) inhibitors, such as AZD0156;    -   CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib),        SRA737, and RG7741 (CHK1/2);    -   CXCR4 antagonists, such as BL-8040, LY2510924, burixafor        (TG-0054), X4P-002, and X4P-001-IO;    -   EXH2 inhibitors, such as GSK2816126;    -   HER2 inhibitors, such as neratinib, and tucatinib (ONT-380);    -   KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, and        GSK-2879552;    -   CXCR2 antagonists, such as AZD-5069;    -   GM-CSF antibodies, such as lenzilumab;    -   DNA dependent protein kinase inhibitors, such as MSC2490484A        (nedisertib), VX-984, and AsiDNA (DT-01);    -   protein kinase C (PKC) inhibitors, such as LXS-196, and        sotrastaurin;    -   Selective estrogen receptor downregulators (SERD), such as        fulvestrant (Faslodex®), RG6046, RG6047, elacestrant (RAD-1901)        and AZD9496;    -   Selective estrogen receptor covalent antagonists (SERCAs), such        as H3B-6545;    -   selective androgen receptor modulator (SARM), such as GTX-024,        and darolutamide;    -   transforming growth factor-beta (TGF-beta) kinase antagonists,        such as galunisertib;    -   anti-transforming growth factor-beta (TGF-beta) antibodies, such        as LY3022859, NIS793, and XOMA 089;    -   bispecific antibodies, such as MM-141 (IGF-1/ErbB3), MM-111        (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD-137/HER2),        AFM26 (BCMA/CD16A), JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3),        RG7802 (CEA/CD3), ERY-974 (CD3/GPC3) vancizumab        (angiopoietins/VEGF), PF-06671008 (Cadherins/CD3), AFM-13        (CD16/CD30), APV0436 (CD123/CD3), flotetuzumab (CD123/CD3),        REGN-1979 (CD20/CD3), MCLA-117 (CD3/CLEC12A), MCLA-128        (HER2/HER3), JNJ-0819, JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3),        MGD-013 (PD-1/LAG-3), AK-104 (CTLA-4/PD-1), AMG-330 (CD33/CD3),        AMG-420 (BCMA/CD3), BI-836880 (VEFG/ANG2), JNJ-63709178        (CD123/CD3), MGD-007 (CD3/gpA33), and MGD-009 (CD3/B7H3);    -   Mutant selective EGFR inhibitors, such as PF-06747775, EGF816        (nazartinib), ASP8273, ACEA-0010, and BI-1482694;    -   Anti-GITR (glucocorticoid-induced tumor necrosis factor        receptor-related protein) antibodies, such as MEDI1873, FPA-154,        INCAGN-1876, TRX-518, BMS-986156, MK-1248, and GWN-323;    -   anti-delta-like protein ligand 3 (DDL3) antibodies, such as        rovalpituzumab tesirine;    -   anti-clusterin antibodies, such as AB-16B5;    -   anti-Ephrin-A4 (EFNA4) antibodies, such as PF-06647263;    -   anti-RANKL antibodies, such as denosumab;    -   anti-mesothelin antibodies, such as BMS-986148, and        Anti-MSLN-MMAE;    -   anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such        as lifastuzumab    -   anti-c-Met antibodies, such as ABBV-399;    -   Adenosine A2A receptor antagonists, such as CPI-444, AZD-4635,        preladenant, and PBF-509;    -   Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as        CPI-613;    -   XPO1 inhibitors, such as selinexor (KPT-330);    -   Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib        (AG-221);    -   IDH1 inhibitors such as AG-120, and AG-881 (IDH1 and IDH2),        IDH-305, and BAY-1436032;    -   interleukin-3 receptor (IL-3R) modulators, such as SL-401;    -   Arginine deiminase stimulators, such as pegargiminase        (ADI-PEG-20);    -   antibody-drug conjugates, such as MLN0264 (anti-GCC, guanylyl        cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla),        milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin,        DCDT2980S, polatuzumab vedotin, SGN-CD70A, SGN-CD19A, inotuzumab        ozogamicin, lorvotuzumab mertansine, SAR3419, isactuzumab        govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201        (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402,        177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab        ravtansine, CX-2009, SAR-566658, W-0101, polatuzumab vedotin,        and ABBV-085;    -   claudin-18 inhibitors, such as claudiximab;    -   β-catenin inhibitors, such as CWP-291;    -   anti-CD73 antibodies, such as MEDI-9447 (oleclumab), CPX-006,        IPH-53, and BMS-986179;    -   CD73 antagonists, such as AB-680, PSB-12379, PSB-12441, and        PSB-12425;    -   CD39/CD73 antagonists, such as PBF-1662;    -   chemokine receptor 2 (CCR) inhibitors, such as PF-04136309,        CCX-872, and BMS-813160 (CCR2/CCR5)    -   thymidylate synthase inhibitors, such as ONX-0801;    -   ALK/ROS1 inhibitors, such as lorlatinib;    -   tankyrase inhibitors, such as G007-LK;    -   Mdm2 p53-binding protein inhibitors, such as CMG-097, and        HDM-201;    -   c-PIM inhibitors, such as PIM447;    -   BRAF inhibitors, such as dabrafenib, vemurafenib, encorafenib        (LGX818), and PLX8394;    -   sphingosine kinase-2 (SK2) inhibitors, such as Yeliva®        (ABC294640);    -   cell cycle inhibitors, such as selumetinib (MEK1/2), and        sapacitabine;    -   AKT inhibitors such as MK-2206, ipatasertib, afuresertib,        AZD5363, ARQ-092, capivasertib, and triciribine;    -   anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors, such        as tremelimumab, AGEN-1884, and BMS-986218;    -   c-MET inhibitors, such as AMG-337, savolitinib, tivantinib        (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208,        JNJ-38877618 (OMO-1), merestinib, and HQP-8361;    -   c-Met/VEGFR inhibitors, such as BMS-817378, and TAS-115;    -   c-Met/RON inhibitors, such as BMS-777607;    -   BRAF/EGFR inhibitors, such as BGB-283;    -   bcr/abl inhibitors, such as rebastinib, and asciminib;    -   MNK1/MNK2 inhibitors, such as eFT-508;    -   mTOR inhibitor/cytochrome P450 3A4 stimulators, such as TYME-88    -   lysine-specific demethylase-1 (LSD1) inhibitors, such as        CC-90011;    -   Pan-RAF inhibitors, such as LY3009120, LXH254, and TAK-580;    -   Raf/MEK inhibitors, such as RG7304;    -   CSF1R/KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);    -   kinase inhibitors, such as vandetanib;    -   E selectin antagonists, such as GMI-1271;    -   differentiation inducers, such as tretinoin;    -   epidermal growth factor receptor (EGFR) inhibitors, such as        osimertinib (AZD-9291);    -   topoisomerase inhibitors, such as doxorubicin, daunorubicin,        dactinomycin, eniposide, epirubicin, etoposide, idarubicin,        irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan,        irinotecan, MM-398 (liposomal irinotecan), vosaroxin and        GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib        (ACEA-0010), and irofulven (MGI-114);    -   corticosteroids, such as cortisone, dexamethasone,        hydrocortisone, methylprednisolone, prednisone, and        prednisolone;    -   growth factor signal transduction kinase inhibitors;    -   nucleoside analogs, such as DFP-10917;    -   Ax1 inhibitors, such as BGB-324 (bemcentinib), and SLC-0211;    -   BET inhibitors, such as INCB-054329, INCB057643, TEN-010,        AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib),        NHWD-870, ODM-207,GSK-2820151, GSK-1210151A, ZBC246, ZBC260,        ZEN3694, FT-1101, RG-6146, CC-90010, mivebresib, BI-894999,        PLX-2853, PLX-51107, CPI-0610, and GS-5829;    -   PARP inhibitors, such as olaparib, rucaparib, veliparib,        talazoparib, ABT-767, and BGB-290;    -   Proteasome inhibitors, such as ixazomib, carfilzomib        (Kyprolis®), and marizomi;    -   Glutaminase inhibitors, such as CB-839;    -   Vaccines, such as peptide vaccine TG-01 (RAS), GALE-301,        GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410,        VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S,        SVN53-67/M57-KLH, IMU-131; bacterial vector vaccines such as        CRS-207/GVAX, axalimogene filolisbac (ADXS 11-001); adenovirus        vector vaccines such as nadofaragene firadenovec; autologous        Gp96 vaccine; dendritic cells vaccines, such as CVactm,        stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM,        rocapuldencel-T (AGS-003), DCVAC, CVac™, stapuldencel-T,        eltrapuldencel-T, SL-701, BSKO1TM, ADXS31-142; oncolytic        vaccines such as, talimogene laherparepvec, pexastimogene        devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak,        enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines,        such as CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010,        ProscaVax™; tumor cell vaccines, such as Vigil® (IND-14205),        Oncoquest-L vaccine; live attenuated, recombinant, serotype 1        poliovirus vaccine, such as PVS-RIPO; Adagloxad simolenin;        MEDI-0457; DPV-001 a tumor-derived, autophagosome enriched        cancer vaccine; RNA vaccines such as CV-9209, LV-305; DNA        vaccines, such as MEDI-0457, MVI-816, INO-5401; modified        vaccinia virus Ankara vaccine expressing p53, such as MVA-p53;        DPX-Survivac; BriaVax™; GI-6301; GI-6207; and GI-4000;    -   anti-DLL4 (delta like ligand 4) antibodies, such as demcizumab;    -   STAT-3 inhibitors, such as napabucasin (BBI-608);    -   ATPase p97 inhibitors, such as CB-5083;    -   smoothened (SMO) receptor inhibitors, such as Odomzo®        (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449),        BMS-833923, glasdegib (PF-04449913), LY2940680, and        itraconazole;    -   interferon alpha ligand modulators, such as interferon alpha-2b,        interferon alpha-2a biosimilar (Biogenomics), ropeginterferon        alfa-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon        (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon,        Ro-25-3036), interferon alfa-2a follow-on biologic        (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on        biologic (Biosidus—Bioferon, Citopheron, Ganapar, Beijing Kawin        Technology—Kaferon), Alfaferone, pegylated interferon alpha-1b,        peginterferon alfa-2b follow-on biologic (Amega), recombinant        human interferon alpha-1b, recombinant human interferon        alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN        alpha 2b conjugate, Dynavax (SD-101), and interferon alfa-n1        (Humoferon, SM-10500, Sumiferon);    -   interferon gamma ligand modulators, such as interferon gamma        (OH-6000, Ogamma 100);    -   IL-6 receptor modulators, such as tocilizumab, siltuximab, and        AS-101 (CB-06-02, IVX-Q-101);    -   Telomerase modulators, such as, tertomotide (GV-1001, HR-2802,        Riavax) and imetelstat (GRN-163, JNJ-63935937);    -   DNA methyltransferases inhibitors, such as temozolomide        (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110),        KRX-0402, RX-3117, RRx-001, and azacitidine;    -   DNA gyrase inhibitors, such as pixantrone and sobuzoxane;    -   Bcl-2 family protein inhibitors, such as ABT-263, venetoclax        (ABT-199), ABT-737, and AT-101;    -   Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab        (anti-Notch2/3), and BMS-906024;    -   anti-myostatin inhibitors, such as landogrozumab;    -   hyaluronidase stimulators, such as PEGPH-20;    -   Wnt pathway inhibitors, such as SM-04755, PRI-724, and WNT-974;    -   gamma-secretase inhibitors, such as PF-03084014, MK-0752, and        RO-4929097;    -   Grb-2 (growth factor receptor bound protein-2) inhibitors, such        as BP1001;    -   TRAIL pathway-inducing compounds, such as ONC201, and ABBV-621;    -   Focal adhesion kinase inhibitors, such as VS-4718, defactinib,        and GSK2256098;    -   hedgehog inhibitors, such as saridegib, sonidegib (LDE225),        glasdegib and vismodegib;    -   Aurora kinase inhibitors, such as alisertib (MLN-8237), and        AZD-2811,AMG-900, barasertib, and ENMD-2076;    -   HSPB1 modulators (heat shock protein 27, HSP27), such as        brivudine, and apatorsen;    -   ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803,        VX-970 (berzosertib) and VX-970;    -   mTOR inhibitors, such as sapanisertib and vistusertib (AZD2014),        and ME-344;    -   mTOR/PI3K inhibitors, such as gedatolisib, GSK2141795,        omipalisib, and RG6114;    -   Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112,        and SNX5422;    -   Murine double minute (mdm2) oncogene inhibitors, such as        DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);    -   CD137 agonists, such as urelumab, and utomilumab (PF-05082566);    -   STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454,        SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, and SR-8291;    -   FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877,        AZD4547, JNJ-42756493, LY2874455, and Debio-1347;    -   fatty acid synthase (FASN) inhibitors, such as TVB-2640;    -   Anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102),        and IPH-4102;    -   Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11, and        inebilizumab;    -   CD44 binders, such as A6;    -   protein phosphatease 2A (PP2A) inhibitors, such as LB-100;    -   CYP17 inhibitors, such as seviteronel (VT-464), ASN-001,        ODM-204, CFG920, and abiraterone acetate;    -   RXR agonists, such as IRX4204;    -   hedgehog/smoothened (hh/Smo) antagonists, such as taladegib, and        patidegib;    -   complement C3 modulators, such as Imprime PGG;    -   IL-15 agonists, such as ALT-803, NKTR-255, and hetIL-15;    -   EZH2 (enhancer of zeste homolog 2) inhibitors, such as        tazemetostat, CPI-1205, and GSK-2816126;    -   Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy,        HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev        (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir,        LOAd-703, and OBP-301;    -   DOT1L (histone methyltransferase) inhibitors, such as        pinometostat (EPZ-5676);    -   toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,        Bordetella pertussis adenylate cyclase toxin, diphtheria toxin,        and caspase activators;    -   DNA plasmids, such as BC-819    -   PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);    -   WEEl inhibitors, such as AZD1775 (adavosertib);    -   Rho kinase (ROCK) inhibitors, such as AT13148, and KD025;    -   ERK inhibitors, such as GDC-0994, LY3214996, and MK-8353;    -   IAP inhibitors, such as ASTX660, debio-1143, birinapant,        APG-1387, and LCL-161;    -   RNA polymerase inhibitors, such as lurbinectedin (PM-1183), and        CX-5461;    -   Tubulin inhibitors, such as PM-184, BAL-101553 (lisavanbulin),        OXI-4503, fluorapacin (AC-0001), and plinabulin;    -   Toll-like receptor 4 (TL4) agonists, such as G100, GSK1795091,        and PEPA-10;    -   Elongation factor 1 alpha 2 inhibitors, such as plitidepsin;    -   CD95 inhibitors, such as APG-101, APO-010, and asunercept;    -   WT1 inhibitors, such as DSP-7888;    -   splicing factor 3B subunit1 (SF3B1) inhibitors, such as H3B-8800    -   PDGFR alpha/KIT mutant-specific inhibitors such as BLU-285;    -   SHP-2 inhibitors, such as TNO155 (SHP-099), and RMC-4550; and    -   retinoid Z receptor gamma (RORy) agonists, such as LYC-55716;

In some embodiments, provided herein are methods of treating orpreventing a cancer or hyper-proliferative disease in a human or animalhaving or at risk of having the cancer or hyper-proliferative disease isprovided, comprising administering to the human or animal atherapeutically effective amount of a compound of Formula I, II, IIa,III, IV, or V as disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents selected from the group consisting of apoptosissignal-regulating kinase (ASK) inhibitors; Bruton's tyrosine kinase(BTK) inhibitors; cluster of differentiation 47 (CD47) inhibitors;cyclin-dependent kinase (CDK) inhibitors; discoidin domain receptor(DDR) inhibitors; histone deacetylase (HDAC) inhibitors;indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors; Janus kinase(JAK) inhibitors; lysyl oxidase-like protein (LOXL) inhibitors; matrixmetalloprotease (MMP) inhibitors; mitogen-activated protein kinase (MEK)inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors; spleentyrosine kinase (SYK) inhibitors; toll-like receptor 8 (TLR8)inhibitors; toll-like receptor 9 (TLR9) inhibitors; tyrosine-kinaseinhibitors (TKIs), or a pharmaceutically acceptable salt of any of theforegoing, or any combinations thereof. Non-limiting examples include:

-   -   Apoptosis Signal-Regulating Kinase (ASK) Inhibitors: ASK        inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors        include, but are not limited to, those described in WO        2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead        Sciences);    -   Bruton's Tyrosine Kinase (BTK) Inhibitors: Examples of BTK        inhibitors include, but are not limited to,        (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,        acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib,        M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008,        spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459,        DTRMWXHS-12, and TAS-5315;    -   Cluster ofDifferentiation 47 (CD47) inhibitors: Examples of CD47        inhibitors include, but are not limited to anti-CD47 mAbs        (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002,        CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4),        NI-1701, NI-1801, RCT-1938, and TTI-621;    -   Cyclin-dependent Kinase (CDK) Inhibitors: CDK inhibitors include        inhibitors of CDK 1, 2, 3, 4, 6, 7 and 9, such as abemaciclib,        alvocidib (HMR-1275,flavopiridol), AT-7519, dinaciclib, ibrance,        FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor,        UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib,        and TG-02;    -   Discoidin Domain Receptor (DDR) Inhibitors: DDR inhibitors        include inhibitors of DDR1 and/or DDR2. Examples of DDR        inhibitors include, but are not limited to, those disclosed in        WO 2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda        Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO        2013/027802 (Chugai Pharmaceutical), and WO 2013/034933        (Imperial Innovations);    -   Histone Deacetylase (HDAC) Inhibitors: Examples of HDAC        inhibitors include, but are not limited to, abexinostat,        ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055        (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat,        mocetinostat, panobinostat, pracinostat, quisinostat        (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic        acid (VAL-001), vorinostat, tinostamustine, remetinostat, and        entinostat;    -   Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: Examples        of IDO1 inhibitors include, but are not limited to, BLV-0801,        epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod,        NKTR-218, NLG-919-based vaccine, PF-06840003,        pyranonaphthoquinone derivatives (SN-35837), resminostat,        SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and        LY-3381916;    -   Janus Kinase (JAK) Inhibitors: JAK inhibitors inhibit JAK1,        JAK2, and/or JAK3. Examples of JAK inhibitors include, but are        not limited to, AT9283, AZD1480, baricitinib, BMS-911543,        fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544),        INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387),        NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib,        tofacitinib (formerly tasocitinib), INCB052793, and XL019;    -   Lysyl Oxidase-Like Protein (LOXL) Inhibitors: LOXL inhibitors        include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5.        Examples of LOXL inhibitors include, but are not limited to, the        antibodies described in WO 2009/017833 (Arresto Biosciences).        Examples of LOXL2 inhibitors include, but are not limited to,        the antibodies described in WO 2009/017833 (Arresto        Biosciences), WO 2009/035791 (Arresto Biosciences), and WO        2011/097513 (Gilead Biologics);    -   Matrix Metalloprotease (AMP) Inhibitors: MMP inhibitors include        inhibitors of MMP1 through 10. Examples of MMP9 inhibitors        include, but are not limited to, marimastat (BB-2516),        cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and those        described in WO 2012/027721 (Gilead Biologics);    -   Mitogen-activated Protein Kinase (MEK) Inhibitors: MEK        inhibitors include antroquinonol, binimetinib, cobimetinib        (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib,        trametinib (GSK1120212), uprosertib+trametinib, PD-0325901,        pimasertib, LTT462, AS703988, CC-90003, and refametinib;    -   Phosphatidylinositol 3-kinase (PI3K) Inhibitors: PI3K inhibitors        include inhibitors of PI3K7, PI3K6, PI3KO, PI3Ka, and/or        pan-PI3K. Examples of PI3K inhibitors include, but are not        limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY        10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib),        CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0032,        GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib        (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141,        LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604,        rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115,        TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147        (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the        compounds described in WO 2005/113556 (ICOS), WO 2013/052699        (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO        2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead        Calistoga), and WO 2014/201409 (Gilead Sciences);    -   Spleen Tyrosine Kinase (SYK) Inhibitors: Examples of SYK        inhibitors include, but are not limited to,        6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,        BAY-61-3606, cerdulatinib (PRT-062607), entospletinib,        fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343,        tamatinib (R406), GS-9876, and those described in U.S. Pat. No.        8,450,321 (Gilead Connecticut) and those described in U.S.        2015/0175616;    -   Toll-like receptor 8 (TLR8) Inhibitors: Examples of TLR8        inhibitors include, but are not limited to, E-6887, IMO-4200,        IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod,        VTX-1463, and VTX-763;    -   Toll-like receptor 9 (TLR9) Inhibitors: Examples of TLR9        inhibitors include, but are not limited to, AST-008, IMO-2055,        IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042; and    -   Tyrosine-kinase Inhibitors (TKIs): TKIs may target epidermal        growth factor receptors (EGFRs) and receptors for fibroblast        growth factor (FGF), platelet-derived growth factor (PDGF), and        vascular endothelial growth factor (VEGF). Examples of TKIs        include, but are not limited to, afatinib, ARQ-087        (derazantinib), asp5878, AZD3759, AZD4547, bosutinib,        brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib,        dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib,        gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib,        KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin,        nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib,        poziotinib, quizartinib, radotinib, rociletinib, sulfatinib        (HMPL-012), sunitinib, tivoanib, TH-4000, and MEDI-575        (anti-PDGFR antibody).

As used herein, the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy” in the case of treatment with a chemotherapeuticagent) is meant to encompass any non-proteinaceous (i.e., non-peptidic)chemical compound useful in the treatment of cancer. Examples ofchemotherapeutic agents include but are not limited to:

-   -   alkylating agents such as thiotepa and cyclophosphamide        (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and        piposulfan; aziridines such as benzodepa, carboquone,        meturedepa, and uredepa; ethylenimines and methylamelamines        including altretamine, triethylenemelamine,        triethylenephosphoramide, triethylenethiophosphoramide, and        trimemylolomelamine; acetogenins, especially bullatacin and        bullatacinone; a camptothecin, including synthetic analog        topotecan; bryostatin, callystatin; CC-1065, including its        adozelesin, carzelesin, and bizelesin synthetic analogs;        cryptophycins, particularly cryptophycin 1 and cryptophycin 8;        dolastatin; duocarmycin, including the synthetic analogs KW-2189        and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; a        sarcodictyin; spongistatin; nitrogen mustards such as        chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide,        evofosfamide, bendamustine, estramustine, ifosfamide,        mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,        novembichin, phenesterine, prednimustine, trofosfamide, and        uracil mustard; nitrosoureas such as carmustine, chlorozotocin,        foremustine, lomustine, nimustine, and ranimustine; antibiotics        such as the enediyne antibiotics (e.g., calicheamicin,        especially calicheamicin gammaII and calicheamicin phiIl),        dynemicin including dynemicin A, bisphosphonates such as        clodronate, an esperamicin, neocarzinostatin chromophore and        related chromoprotein enediyne antibiotic chromomophores,        aclacinomycins, actinomycin, authramycin, azaserine, bleomycins,        cactinomycin, carabicin, carrninomycin, carzinophilin,        chromomycins, dactinomycin, daunorubicin, detorubicin,        6-diazo-5-oxo-L-norleucine, doxorubicin (including        morpholino-doxorubicin, cyanomorpholino-doxorubicin,        2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin,        esorubicin, idarubicin, marcellomycin, mitomycins such as        mitomycin C, mycophenolic acid, nogalamycin, olivomycins,        peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin,        streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin,        and zorubicin; anti-metabolites such as methotrexate and        5-fluorouracil (5-FU); folic acid analogs such as demopterin,        methotrexate, pteropterin, and trimetrexate; purine analogs such        as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;        pyrimidine analogs such as ancitabine, azacitidine,        6-azauridine, carmofur, cytarabine, dideoxyuridine,        doxifluridine, enocitabine, and floxuridine; androgens such as        calusterone, dromostanolone propionate, epitiostanol,        mepitiostane, and testolactone; anti-adrenals such as        aminoglutethimide, mitotane, and trilostane; folic acid        replinishers such as frolinic acid; radiotherapeutic agents such        as Radium-223; trichothecenes, especially T-2 toxin, verracurin        A, roridin A, and anguidine; taxoids such as paclitaxel        (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel,        BIND-014, tesetaxel; platinum analogs such as cisplatin and        carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide        glycoside; aminolevulinic acid; eniluracil; amsacrine;        hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;        diaziquone; elformthine; elliptinium acetate; an epothilone;        etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin;        lonidamine; maytansinoids such as maytansine and ansamitocins;        mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;        phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic        acid; podophyllinic acid; 2-ethylhydrazide; procarbazine;        polysaccharide-K (PSK); razoxane; rhizoxin; sizofiran;        spirogermanium; tenuazonic acid; trabectedin, triaziquone;        2,2′,2″-tricUorotriemylamine; urethane; vindesine; dacarbazine;        mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;        arabinoside (“Ara-C”); cyclophosphamide; thiopeta; chlorambucil;        gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine;        methotrexate; vinblastine; platinum; etoposide (VP-16);        ifosfamide; mitroxantrone; vancristine; vinorelbine        (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin;        aminopterin; xeoloda; ibandronate; CPT-11; topoisomerase        inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids        such as retinoic acid; capecitabine; NUC-1031; FOLFIRI        (fluorouracil, leucovorin, and irinotecan); and pharmaceutically        acceptable salts, acids, or derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” areanti-hormonal agents such as anti-estrogens and selective estrogenreceptor modulators (SERMs), inhibitors of the enzyme aromatase,anti-androgens, and pharmaceutically acceptable salts, acids orderivatives of any of the above that act to regulate or inhibit hormoneaction on tumors.

Anti-Hormonal Agents

Examples of anti-estrogens and SERMs include, for example, tamoxifen(including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and toremifene(FARESTON®).

Inhibitors of the enzyme aromatase regulate estrogen production in theadrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide,megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole(RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

Examples of anti-androgens include apalutamide, abiraterone,enzalutamide, flutamide, galeterone, nilutamide, bicalutamide,leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

Examples of progesterone receptor antagonist include onapristone.

Anti-Angiogenic Agents

Anti-angiogenic agents include, but are not limited to, retinoid acidand derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®,regorafenib, necuparanib, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism including proline analogs such as 1-azetidine-2-carboxylicacid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,α,α′-dipyridyl, beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chicken inhibitor ofmetalloproteinase-3 (ChTVIP-3), chymostatin, beta-cyclodextrintetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate,d-penicillamine, beta-i-anticollagenase-serum, alpha-2-antiplasmin,bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilicacid disodium or “CCA”, thalidomide, angiostatic steroid, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, andinhibitors of S100A9 such as tasquinimod. Other anti-angiogenesis agentsinclude antibodies, preferably monoclonal antibodies against theseangiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms,VEGF-C, HGF/SF, and Ang-1/Ang-2.

Anti-Fibrotic Agents

Anti-fibrotic agents include, but are not limited to, the compounds suchas beta-aminoproprionitrile (BAPN), as well as the compounds disclosedin U.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase andtheir use in the treatment of diseases and conditions associated withthe abnormal deposition of collagen and U.S. Pat. No. 4,997,854 relatingto compounds which inhibit LOX for the treatment of various pathologicalfibrotic states, which are herein incorporated by reference. Furtherexemplary inhibitors are described in U.S. Pat. No. 4,943,593 relatingto compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine,U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and US2004-0248871, which are herein incorporated by reference.

Exemplary anti-fibrotic agents also include the primary amines reactingwith the carbonyl group of the active site of the lysyl oxidases, andmore particularly those which produce, after binding with the carbonyl,a product stabilized by resonance, such as the following primary amines:emylenemamine, hydrazine, phenylhydrazine, and their derivatives;semicarbazide and urea derivatives; aminonitriles such as BAPN or2-nitroethylamine; unsaturated or saturated haloamines such as2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine,3-bromopropylamine, and p-halobenzylamines; and selenohomocysteinelactone.

Other anti-fibrotic agents are copper chelating agents penetrating ornot penetrating the cells. Exemplary compounds include indirectinhibitors which block the aldehyde derivatives originating from theoxidative deamination of the lysyl and hydroxylysyl residues by thelysyl oxidases. Examples include the thiolamines, particularlyD-penicillamine, and its analogs such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate, andsodium-4-mercaptobutanesulphinate trihydrate.

Immunotherapeutic Agents

Examples of immunotherapeutic agents include but are not limited totherapeutic antibodies suitable for treating patients. Some examples oftherapeutic antibodies include abagovomab, ABP-980, adecatumumab,afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab,bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab,brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab,cixutumumab, clivatuzumab, conatumumab, dacetuzumab, dalotuzumab,daratumumab, detumomab, dinutuximab, drozitumab, duligotumab,dusigitumab, ecromeximab, elotuzumab, emibetuzumab, ensituximab,ertumaxomab, etaracizumab, farletuzumab, ficlatuzumab, figitumumab,flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab,glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab,inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, andMDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab,lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab,minretumomab, mitumomab, mogamulizumab, moxetumomab, naptumomab,narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833,obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox,patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab,samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab,tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab,tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab,vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab can be used fortreating indolent B-cell cancers, including marginal-zone lymphoma, WM,CLL and small lymphocytic lymphoma. In some embodiments, a combinationof Rituximab and chemotherapy agents is especially effective.

The exemplified therapeutic antibodies may be further labeled orcombined with a radioisotope particle such as indium-111, yttrium-90(90Y-clivatuzumab), or iodine-131.

Cancer Gene Therapy and Cell Therapy

Cancer gene therapy and cell therapy include the insertion of a normalgene into cancer cells to replace a mutated or altered gene; geneticmodification to silence a mutated gene; genetic approaches to directlykill the cancer cells; including the infusion of immune cells designedto replace most of the patient's own immune system to enhance the immuneresponse to cancer cells, or activate the patient's own immune system (Tcells or Natural Killer cells) to kill cancer cells, or find and killthe cancer cells; and genetic approaches to modify cellular activity tofurther alter endogenous immune responsiveness against cancer.

Gene Editors

Examples of genome editing system include a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system,and a meganuclease system.

CAR-T Cell Therapy and TCR-T Cell Therapy

CAR-T cell therapy includes a population of immune effector cellsengineered to express a chimeric antigen receptor (CAR), wherein the CARcomprises a tumor antigen-binding domain. The immune effector cell is aT cell or an NK cell. TCR-T cell therapy includes TCR-T cells that areengineered to target tumor derived peptides present on the surface oftumor cells. Cells can be autologous or allogeneic.

In some embodiments, the CAR comprises an antigen binding domain, atransmembrane domain, and an intracellular signaling domain.

In some embodiments, the intracellular domain comprises a primarysignaling domain, a costimulatory domain, or both of a primary signalingdomain and a costimulatory domain.

In some embodiments, the primary signaling domain comprises a functionalsignaling domain of one or more proteins selected from the groupconsisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcRgamma (FCERIG), FcR beta (Fc Epsilon Rlb), CD79a, CD79b, Fcgamma RIIa,DAP10, and DAP12.

In some embodiments, the costimulatory domain comprises a functionaldomain of one or more proteins selected from the group consisting ofCD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocytefunction-associated antigen-1 (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, aligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM(LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, CD4, CD8alpha, CD8beta,IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4,CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 ld, ITGAE, CD103, ITGAL, CD 1la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18,LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4),CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1,CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150,IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76,PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D.

In some embodiments, the transmembrane domain comprises a transmembranedomain of a protein selected from the group consisting of the alpha,beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4,CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137,CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD1 la, CD18), ICOS (CD278),4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1),CD160, CD19, IL2R beta, IL2R gamma, IL7R u, ITGA1, VLA1, CD49a, ITGA4,IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 ld, ITGAE, CD103, ITGAL, CD1la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 lc, ITGB1, CD29, ITGB2, CD18,LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100(SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME(SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D, andNKG2C.

In some embodiments, the antigen binding domain binds a tumor antigen.

In some embodiments, the tumor antigen is selected from the groupconsisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to asCD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); C-type lectin-likemolecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptorvariant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3(aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); TNF receptor familymember B cell maturation (BCMA); Tn antigen ((Tn Ag) or(GaINAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); Receptortyrosine kinase-like orphan receptor 1 (RORI); Fms-Like, Tyrosine Kinase3 (FLT3); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6;Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule(EPCAM); B7H3 (CD276); KIT (CD 117); Interleukin-13 receptor subunitalpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha(IL-11Ra); prostate stem cell antigen (PSCA); Protease Serine 21(Testisin or PRSS21); vascular endothelial growth factor receptor 2(VEGFR2); Lewis(Y)antigen; CD24; Platelet-derived growth factor receptorbeta (PDGFR-beta); Stage-specificembryonic antigen-4 (SSEA-4); CD20;delta like 3 (DLL3); Folate receptor alpha; Receptor tyrosine-proteinkinase, ERBB2 (Her2/neu); Mucin 1, cell surface associated (MUC1);epidermal growth factor receptor (EGFR); neural cell adhesion molecule(NCAM); Prostase; prostatic acid phosphatase (PAP); elongation factor 2mutated (ELF2M); Ephrin B2; fibroblast activation protein alpha (FAP);insulin-like growth factor 1 receptor (IGF-I receptor), carbonicanhydrase IX (CAIX); Proteasome (Prosome, Macropain) Subunit, Beta Type,9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consistingof breakpoint cluster region (BCR) and Abelson murineleukemia viraloncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2(EphA2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); gangliosideGM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5);high molecular weight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1(TEM1/CD248); tumor endothelial marker 7-related (TEM7R); sixtransmembrane epithelial antigen of the prostate I (STEAP1); claudin 6(CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupledreceptor class C group 5, member D (GPRCSD); chromosome X open readingframe 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK);Polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide portion ofgloboH glycoceramide (GloboH); mammary gland differentiation antigen(NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1(HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3 (PANX3); Gprotein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locusK 9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCR Gamma AlternateReading Frame Protein (TARP); Wilms tumor protein (WT1); Cancer/testisantigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-1a);Melanomaassociated antigen 1 (MAGE-A1); ETS translocation-variant gene6, located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); XAntigen Family, Member 1A (XAGE1); angiopoietin-binding cell surfacereceptor 2 (Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanomacancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor proteinp53, (p53); p53 mutant; prostein; survivin; telomerase; prostatecarcinoma tumor antigen-1 (PCTA-1 or Galectin 8), melanoma antigenrecognized by T cells 1 (MelanA or MARTI); Rat sarcoma (Ras) mutant;human Telomerase reverse transcriptase (hTERT); sarcoma translocationbreakpoints; melanoma inhibitor of apoptosis (ML-IAP); ERG(transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-Acetylglucosaminyl-transferase V (NA17); paired box protein Pax-3 (PAX3);Androgen receptor; Cyclin B1; v-myc avian myelocytomatosis viraloncogene neuroblastoma derived homolog (MYCN); Ras Homolog Family MemberC (RhoC); Tyrosinase-related protein 2 (TRP-2); Cytochrome P450 1B1 (CYPIBI); CCCTC-Binding Factor (Zinc Finger Protein)-Like (BORIS or Brotherof the Regulator of Imprinted Sites), Squamous Cell Carcinoma AntigenRecognized By T Cells 3 (SART3); Paired box protein Pax-5 (PAX5);proacrosin binding protein sp32 (OY-TES I); lymphocyte-specific proteintyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); synovialsarcoma, X breakpoint 2 (SSX2); Receptor for Advanced GlycationEndproducts (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2(RU2); legumain; human papilloma virus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associatedimmunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor(FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily Amember 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-typelectin domain family 12 member A (CLEC12A); bone marrow stromal cellantigen 2 (BST2); EGF-like modulecontaining mucin-like hormonereceptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-3 (GPC3);Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1(IGLL1).

In some embodiments, the tumor antigen is selected from CD150, 5T4,ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148,CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261,CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5,CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1,CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2,ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 in combination, HER2-HER3 incombination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelopeglycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2/neu, IGF-1R,IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii,L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1,MART-1, MUC1, NKG2C ligands, NKG2D Ligands, NYESO-1, OEPHa2, PIGF, PSCA,PSMA, ROR1, T101, TAC, TAG72, TTM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, a G-protein coupled receptor,alphafetoprotein (AFP), an angiogenesis factor, an exogenous cognatebinding molecule (ExoCBM), oncogene product, anti-folate receptor,c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2,epithelial tumor antigen, estrogen receptor, fetal acethycholine ereceptor, folate binding protein, gp100, hepatitis B surface antigen,kappa chain, kappa light chain, kdr, lambda chain, livin,melanoma-associated antigen, mesothelin, mouse double minute 2 homolog(MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens,oncofetal antigen, ROR2, progesterone receptor, prostate specificantigen, tEGFR, tenascin, P2-Microgiobuiin, and Fc Receptor-like 5(FcRL5).

Non limiting examples of cell therapies include Algenpantucel-L,Sipuleucel-T, (BPX-501) rivogenlecleucel U.S. Pat. No. 9,089,520,WO2016100236, AU-105, ACTR-087, activated allogeneic natural killercells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007,UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema,FT-1050-treated bone marrow stem cell therapy, CD4CARNK-92 cells,CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22cells, EGFRt/19-28z/4-1BBL CAR T cells, autologous 4H11-28z/fIL-12/EFGRtT cell, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T,Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503,CMD-504, CMD-502, CMD-601, CMD-602, and CSG-005.

In some embodiments, the tumor targeting antigen includes:Alpha-fetoprotein, such as ET-1402, and AFP-TCR; Anthrax toxin receptor1, such as anti-TEM8 CAR T-cell therapy; B cell maturation antigens(BCMA), such as bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998,LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101,and AUTO-2 (APRIL-CAR; Anti-CLL-1 antibodies, such as KITE-796; B7homolog 6, such as CAR-NKp30 and CAR-B7H6; B-lymphocyte antigen CD19,such as TBI-1501, CTL-119 huCART-19 T cells, JCAR-015 U.S. Pat. No.7,446,190, JCAR-014, JCAR-017, (WO2016196388, WO2016033570,WO2015157386), axicabtagene ciloleucel (KTE-C19), U.S. Pat. Nos.7,741,465, 6,319,494, UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019),WO2012079000, WO2017049166, CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcells, CD19/4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19,CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, and IM19 CAR-T;B-lymphocyte antigen CD20, such as ATTCK-20; B-lymphocyte cell adhesion,such as UCART-22, and JCAR-018 (WO2016090190); NY-ESO-1, such asGSK-3377794, and TBI-1301; Carbonic anhydrase, such as DC-Ad-GMCAIX;Caspase 9 suicide gene, such as CaspaCIDe DLI, and BPX-501; CCR5, suchas SB-728; CDw123, such as MB-102, and UCART-123; CD20m such asCBM-C20.1; CD4, such as ICG-122; CD30, such as CART30 (CBM-C30.1); CD33,such as CIK-CAR.CD33; CD38, such as T-007, and UCART-38; CD40 ligand,such as BPX-201; CEACAM protein 4 modulators, such as MG7-CART; Claudin6, such as CSG-002; EBV targeted, such as CMD-003; EGFR, such asautologous 4H11-28z/fIL-12/EFGRt T cell; Endonuclease, such as PGN-514,and PGN-201; Epstein-Barr virus specific T-lymphocytes, such as TT-10;Erbb2, such as CST-102 and CIDeCAR; Ganglioside (GD2), such as4SCAR-GD2; Glutamate carboxypeptidase II, such as CIK-CAR.PSMA,CART-PSMA-TGFBRDN, and P-PSMA-101; Glypican-3 (GPC3), such as TT-16 andGLYCAR; Hemoglobin, such as PGN-236; Hepatocyte growth factor receptor,such as anti-cMet RNA CAR T; Human papillomavirus E7 protein, such asKITE-439; Immunoglobulin gamma Fc receptor III, such as ACTR087; IL-12,such as DC-RTS-IL-12; IL-12 agonist/mucin 16, such as JCAR-020; IL-13alpha 2, such as MB-101; IL-2, such as CST-101; K-Ras GTPase, such asanti-KRAS G12V mTCR cell therapy; Neural cell adhesion molecule L1 L1CAM(CD171), such as JCAR-023; Latent membrane protein 1/Latent membraneprotein 2, such as Ad5f35-LMPd1-2-transduced autologous dendritic cells;Melanoma associated antigen 10, such as MAGE-A10C796T and MAGE-A10 TCR;Melanoma associated antigen 3/Melanoma associated antigen 6 (MAGE A3/A6)such as KITE-718; Mesothelin, such as CSG-MESO and TC-210; NKG2D, suchas NKR-2; Ntrkr1 tyrosine kinase receptor, such as JCAR-024; T cellreceptors, such as BPX-701 and IMCgp100; T-lymphocyte, such as TT-12;Tumor infiltrating lymphocytes, such as LN-144 and LN-145; and Wilmstumor protein, such as JTCR-016, WT1-CTL.

Lymphoma or Leukemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating lymphoma or leukemia. These agents include aldesleukin,alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10,antineoplaston AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2family protein inhibitor ABT-263, beta alethine, BMS-345541, bortezomib(VELCADE®), bortezomib (VELCADE®, PS-341), bryostatin 1, bulsulfan,campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine,caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide,doxorubicin, vincristine, and prednisone), cisplatin, cladribine,clofarabine, curcumin, CVP (cyclophosphamide, vincristine, andprednisone), cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin,doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide,cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin,epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine,cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide,and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR(fludarabine and rituximab), geldanamycin (17-AAG), hyperCVAD(hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide,carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride,interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013),lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil, andprednisolone), melphalan, mesna, methotrexate, mitoxantronehydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine,obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fattyacids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib(PD0332991), pegfilgrastim, PEGylated liposomal doxorubicinhydrochloride, perifosin, prednisolone, prednisone, recombinant flt3ligand, recombinant human thrombopoietin, recombinant interferon alfa,recombinant interleukin-11, recombinant interleukin-12, rituximab,R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximaband FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP),R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate,simvastatin, sirolimus, styryl sulphones, tacrolimus, tanespimycin,temsirolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes,thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbineditartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, andhydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

One modified approach is radioimmunotherapy, wherein a monoclonalantibody is combined with a radioisotope particle, such as indium-111,yttrium-90, and iodine-131. Examples of combination therapies include,but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

The above-mentioned therapies can be supplemented or combined with stemcell transplantation or treatment. Therapeutic procedures includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechnique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and non-myeloablative allogeneichematopoietic stem cell transplantation.

Non-Hodgkin's Lymphomas Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating non-Hodgkin's lymphomas (NHL), especially those of B cellorigin, which include monoclonal antibodies, standard chemotherapyapproaches (e.g., CHOP, CVP, FCM, MCP, and the like),radioimmunotherapy, and combinations thereof, especially integration ofan antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies for the treatment ofNHL/B-cell cancers include rituximab, alemtuzumab, human or humanizedanti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducingligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, andanti-CD74.

Examples of experimental antibody agents used in treatment of NHL/B-cellcancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab,SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab,and bevacizumab.

Examples of standard regimens of chemotherapy for NHL/B-cell cancersinclude CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

Mantle Cell Lymphoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating mantle cell lymphoma (MCL), which include combinationchemotherapies such as CHOP, hyperCVAD, and FCM. These regimens can alsobe supplemented with the monoclonal antibody rituximab to formcombination therapies R-CHOP, hyperCVAD-R, and R-FCM. Any of theabove-mentioned therapies may be combined with stem cell transplantationor ICE in order to treat MCL.

Other examples of therapeutic agents suitable for treating MCL include:

-   -   immunotherapy, such as monoclonal antibodies (like rituximab)        and cancer vaccines, such as GTOP-99, which are based on the        genetic makeup of an individual patient's tumor;    -   radioimmunotherapy, wherein a monoclonal antibody is combined        with a radioisotope particle, such as iodine-131 tositumomab        (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and        BEXXAR® in sequential treatment with CHOP;    -   autologous stem cell transplantation coupled with high-dose        chemotherapy, administering proteasome inhibitors such as        bortezomib (VELCADE® or PS-341), or administering        antiangiogenesis agents such as thalidomide, especially in        combination with rituximab;    -   drugs that lead to the degradation of Bcl-2 protein and increase        cancer cell sensitivity to chemotherapy, such as oblimersen, in        combination with other chemotherapeutic agents;    -   mTOR inhibitors, which can lead to inhibition of cell growth and        even cell death. Non-limiting examples are sirolimus,        temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126,        PQR-309 (bimiralisib), voxtalisib, GSK-2126458, and temsirolimus        in combination with RITUXAN®, VELCADE®, or other        chemotherapeutic agents;    -   other agents such as flavopiridol, palbociclib (PD0332991),        R-roscovitine (selicicilib, CYC202), styryl sulphones, obatoclax        (GX15-070), TRAIL, Anti-TRAIL death receptors DR4 and DR5        antibodies, temsirolimus (TORISEL®, CCl-779), everolimus        (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide        (REVLIMID®, CC-5013), and geldanamycin (17-AAG).

Waldenstrom's Macroglobulinemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating Waldenstrom's Macroglobulinemia (WM), which includealdesleukin, alemtuzumab, alvocidib, amifostine trihydrate,aminocamptothecin, antineoplaston A10, antineoplaston AS2-1,anti-thymocyte globulin, arsenic trioxide, autologous humantumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, betaalethine, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H,carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin,clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicinhydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab(hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide,filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibodyMN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone,lymphokine-activated killer cells, melphalan, mesna, methotrexate,mitoxantrone hydrochloride, monoclonal antibody CD19 (such astisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20,motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen,octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel,pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride,pentostatin, perifosine, prednisone, recombinant flt3 ligand,recombinant human thrombopoietin, recombinant interferon alfa,recombinant interleukin-11, recombinant interleukin-12, rituximab,sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus,tacrolimus, tanespimycin, thalidomide, therapeutic allogeneiclymphocytes, thiotepa, tipifarnib, tositumomab, veltuzumab, vincristinesulfate, vinorelbine ditartrate, vorinostat, WT1 126-134 peptidevaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan,yttrium-90 humanized epratuzumab, and any combinations thereof.

Other examples of therapeutic procedures used to treat WM includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechniques, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and nonmyeloablative allogeneichematopoietic stem cell transplantation.

Diffuse Large B-Cell Lymphoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating diffuse large B-cell lymphoma (DLBCL), which includecyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20monoclonal antibodies, etoposide, bleomycin, many of the agents listedfor WM, and any combination thereof, such as ICE and R-ICE.

Chronic Lymphocytic Leukemia Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating chronic lymphocytic leukemia (CLL), which include chlorambucil,cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin,vincristine, prednisone, prednisolone, alemtuzumab, many of the agentslisted for WM, and combination chemotherapy and chemoimmunotherapy,including the following common combination regimens: CVP, R-CVP, ICE,R-ICE, FCR, and FR.

Myelofibrosis Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating myelofibrosis, which include hedgehog inhibitors, histonedeacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors.Non-limiting examples of hedgehog inhibitors are saridegib andvismodegib.

Examples of HDAC inhibitors include, but are not limited to, pracinostatand panobinostat.

Non-limiting examples of tyrosine kinase inhibitors includelestaurtinib, bosutinib, imatinib, gilteritinib, radotinib, andcabozantinib.

Hyperproliferative Disease Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating a hyper-proliferative disease, which include gemcitabine,nab-paclitaxel, and gemcitabine/nab-paclitaxel with a JAK inhibitorand/or PI3K6 inhibitor.

Bladder Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating bladder cancer, which include atezolizumab, carboplatin,cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine,idosfamide, Interferon alfa-2b, methotrexate, mitomycin, nab-paclitaxel,paclitaxel, pemetrexed, thiotepa, vinblastine, and any combinationsthereof.

Breast Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating breast cancer, which include albumin-bound paclitaxel,anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide,docetaxel, doxorubicin, epirubicin, everolimus, exemestane,fluorouracil, fulvestrant, gemcitabine, Ixabepilone, lapatinib,Letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomaldoxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab,vinorelbine, and any combinations thereof.

Triple Negative Breast Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating triple negative breast cancer, which include cyclophosphamide,docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, andcombinations thereof.

Colorectal Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating colorectal cancer, which include bevacizumab, capecitabine,cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin,panitumumab, ziv-aflibercept, and any combinations thereof.

Castration-Resistant Prostate Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating castration-resistant prostate cancer, which includeabiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone,sipuleucel-T, and any combinations thereof.

Esophageal and Esophagogastric Junction Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating esophageal and esophagogastric junction cancer, which includecapecitabine, carboplatin, cisplatin, docetaxel, epirubicin,fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin,paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Gastric Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating gastric cancer, which include capecitabine, carboplatin,cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil,Irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab,trastuzumab, and any combinations thereof.

Head & Neck Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating head & neck cancer, which include afatinib, bleomycin,capecitabine, carboplatin, cetuximab, cisplatin, docetaxel,fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab,paclitaxel, pembrolizumab, vinorelbine, and any combinations thereof.

Hepatobiliary Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating hepatobiliary cancer, which include capecitabine, cisplatin,fluoropyrimidine, 5-fluorourcil, gemecitabine, oxaliplatin, sorafenib,and any combinations thereof.

Hepatocellular Carcinoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating hepatocellular carcinoma, which include capecitabine,doxorubicin, gemcitabine, sorafenib, and any combinations thereof.

Non-Small Cell Lung Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating non-small cell lung cancer (NSCLC), which include afatinib,albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab,cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel,erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab,pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib,vemurafenib, vinblastine, vinorelbine, and any combinations thereof.

Small Cell Lung Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating small cell lung cancer (SCLC), which include bendamustime,carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin,etoposide, gemcitabine, ipillimumab, irinotecan, nivolumab, paclitaxel,temozolomide, topotecan, vincristine, vinorelbine, and any combinationsthereof.

Melanoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating melanoma, which include albumin bound paclitaxel, carboplatin,cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib,interferon alfa-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel,pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib,vinblastine, and any combinations thereof.

Ovarian Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating ovarian cancer, which include 5-flourouracil, albumin boundpaclitaxel, altretamine, anastrozole, bevacizumab, capecitabine,carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin,etoposide, exemestane, gemcibabine, ifosfamide, irinotecan, letrozole,leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan,olaparib, oxaliplatin, paclitaxel, Pazopanib, pemetrexed, tamoxifen,topotecan, vinorelbine, and any combinations thereof.

Pancreatic Cancer Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating pancreatic cancer, which include 5-fluorourcil, albumin-boundpaclitaxel, capecitabine, cisplatin, docetaxel, erlotinib,fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin,paclitaxel, and any combinations thereof.

Renal Cell Carcinoma Combination Therapy

In some embodiments, the additional therapeutic agents are suitable fortreating renal cell carcinoma, which include axitinib, bevacizumab,cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib,sorafenib, sunitinib, temsirolimus, and any combinations thereof.

VII. Compound Preparation

Some embodiments of the present disclosure are directed to processes andintermediates useful for preparing the compounds provided herein orpharmaceutically acceptable salts thereof.

Compounds described herein can be purified by any of the means known inthe art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography.

During any of the processes for preparation of the compounds providedherein, it may be necessary and/or desirable to protect sensitive orreactive groups on any of the molecules concerned. This may be achievedby means of conventional protecting groups as described in standardworks, such as T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” 4^(th) ed., Wiley, New York 2006. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used.

The methods of the present disclosure generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordisatereomerically pure.

Representative syntheses of compounds of the present disclosure aredescribed in the schemes below, and the particular examples that follow.

List of Abbreviations and Acronyms

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl ACN or MeCNAcetonitrile AcOH Acetic acid aq. Aqueous Ar Argon ATP Adenosinetriphosphate Boc tert-butyloxycarbonyl br Broad CH₂Cl₂ DichloromethaneCH(OCH₃)₃ Trimethyl orthoformate c-Pr or c-propyl cyclopropyl d Doubletor deuterated DCE Dichloroethene DCM or CH₂Cl₂ Dichloromethane ddDoublet of doublets DIEA or DIPEA Diisopropylethylamine DMAc or DMADimethylacetamide DMF Dimethylformamide DMSO Dimethylsulfoxide DMEDimethoxyethane dt Doublet-triplet eq Equivalents ES/MS Electrospraymass spectrometry Et Ethyl EA or EtOAc Ethyl acetate g Grams HATU1-[Bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HCOOH Formic acid Hex Hexanes HPLC Highpressure liquid chromatography hr or h or hrs Hours Hz Hertz IPAIsopropyl alcohol i-Pr Isopropyl J Coupling constant (MHz) K₂CO₃Potassium carbonate Kg or kg Kilogram L Liter LCMS or LC-MS Liquidchromatography-mass spectrometry M Molar m multiplet M+ Mass peak M + H+Mass peak plus hydrogen Me Methyl MeOH Methanol mg Milligram MHzMegahertz ml or mL Milliliter mM Millimolar mmol Millimole mol Mole MSMass spectroscopy Ms methanesulfonyl N Normal NaH Sodium hydride n-Bu orBu Butyl NH₄Cl Ammonium Chloride NMR Nuclear magnetic resonance NMPN-methylpyrrolidinone Pd—C/Pd/C Palladium on Carbon Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium PE Petroleum ether Ph Phenyl qQuartet RP Reverse phase RT or rt Room temperature s Singlet sat. orsatd. Saturated sec-Bu sec-Butyl t Triplet T3P Propylphosphonicanhydride solution TEA Triethylamine t-Bu or tert-Bu or t-butyltert-Butyl TFA Trifluoroacetic acid THF Tetrahydrofuran TR-FRETTime-resolved fluorescence energy transfer δ Chemical shift (ppm) μL orμl Microliter μM Micromolar

General Synthetic Schemes

General Reaction Schemes I, II, III, IV, and V are provided as furtherembodiments of the present disclosure and illustrate general methodswhich were used to prepare certain compounds of the present disclosureand which can be used to prepare additional compounds of the presentdisclosure. Each of the variables (e.g., R¹, R², R³, R⁴) of formulas(1)-(20) are as defined herein.

The compounds of the present disclosure may be prepared using themethods disclosed herein and routine modifications thereof, which willbe apparent to a skilled artisan given the disclosure herein and methodswell known in the art. Conventional and well-known synthetic methods maybe used in addition to the teachings herein. The synthesis of typicalcompounds described herein may be accomplished as described in thefollowing examples. If available, reagents may be purchasedcommercially, e.g., from Sigma Aldrich or other chemical suppliers. Ingeneral, compounds described herein are typically stable and isolatableat room temperature and pressure.

Typical embodiments of compounds disclosed herein may be synthesizedusing the general reaction schemes described below. It will be apparentto a skilled artisan given the description herein that the generalschemes may be altered by substitution of the starting materials withother materials having similar structures to result in products that arecorrespondingly different. Descriptions of syntheses follow to providenumerous examples of how the starting materials may vary to providecorresponding products. Given a desired product for which thesubstituent groups are defined, the necessary starting materialsgenerally may be determined by inspection. Starting materials aretypically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodimentsdisclosed in the present disclosure, inspection of the structure of thecompound to be synthesized will provide the identity of each substituentgroup. The identity of the final product will generally render apparentthe identity of the necessary starting materials by a simple process ofinspection, given the examples herein.

The terms “solvent”, “inert organic solvent”, or “inert solvent” referto a solvent inert under the conditions of the reaction being describedin conjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, and the like). Unless specified to the contrary, the solventsused in the reactions of the present disclosure are inert organicsolvents, and the reactions are carried out under an inert gas,preferably nitrogen or argon.

Reaction Scheme I

The compounds of Formula I may be prepared using the methods similar tothe Reaction Scheme I shown below.

Step 1—Preparation of a Compound of Formula (3)

The compounds of formula (3) can be made by combining compounds (1) and(2). Compounds (1) and (2) are commercially available or can be made bymethods known in the art. Compounds (1) and (2) can be mixed in asuitable solvent such as THF. After stirring at a temperature between 0°C. and 100° C. for between 10 min and 24 h or until reaction iscomplete, the reaction is allowed to cool to room temperature. Thecompound of formula (3) can be obtained by filtration or precipitation.

Step 2—Preparation of a Compound of Formula (4)

The compounds of formula (4) may be prepared by chlorination of thecompounds of formula (3) by methods known in the art. A compound offormula (3) may be mixed with POCl₃ in a suitable solvent such astoluene. After stirring at a temperature between 0° C. and 100° C. forbetween 10 min and 24 h or until reaction is complete, the reaction isallowed to cool to room temperature. The solvent can then be removedunder reduced pressure. To extract the compound of formula (4), anorganic solvent such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated to obtainthe compound of formula (4). The compound of formula (4) may be purifiedby any suitable methods known in the art such as chromatography onsilica gel, trituration, precipitation, or crystallization.

Step 3—Preparation of a Compound of Formula (5)

The compounds of formula (5) may be prepared by reduction of thecompounds of formula (4) by methods known in the art. A compound offormula (4) can be mixed with Zinc dust and ammonium chloride insuitable solvent such as THF, MeOH, or water, or a mixture of solventconsisting of THF, MeOH, and water. After stirring at a temperaturebetween 0° C. and 100° C. for between 1 h and 24 h or until reaction iscomplete, the reaction is allowed to cool to room temperature andfiltered through celite bed. To extract the compound of formula (5), anorganic solvent such as ethyl acetate may be added, followed by washingwith water and brine. The organic phase can be concentrated to obtainthe compound of formula (5). The compound of formula (5) may be purifiedby any suitable methods known in the art such as chromatography onsilica gel, trituration, precipitation, or crystallization.

Step 4—Preparation of a Compound of Formula (6)

The compounds of formula (6) may be prepared by cyclization of thecompounds of formula (5) by methods known in the art. A compound offormula (5) can be mixed with trimethyl orthoformate and formic acid.After stirring at a temperature between 0° C. and 100° C. for between 1h and 24 h or until reaction is complete, the remaining solvent isremoved via distillation. To extract the compound of formula (6), anorganic solvent such as dichloromethane may be added, followed bywashing with water and brine. The organic phase can be concentrated toobtain the compound of formula (6). The compound of formula (6) may bepurified by any suitable methods known in the art such as chromatographyon silica gel, trituration, precipitation, crystallization, or washingwith organic solvent such as ether including but not limited to methylt-butyl ether.

Step 5—Preparation of a Compound of Formula (7)

The compounds of formula (7) may be prepared by fluorination of thecompounds of formula (6) by methods known in the art. A compound offormula (6) can be mixed with cesium fluoride in a solvent such DMF.After stirring at a temperature between room temperature and 110° C. forbetween 1 h and 24 h or until reaction is complete, the reaction iscooled to between 0° C. and room temperature by adding ice water or byadding the reaction mixture to ice water. To extract the compound offormula (7), an organic solvent such as ethyl acetate may be added,followed by washing with water and brine. The organic phase can beconcentrated to obtain the compound of formula (7). The compound offormula (7) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation, orcrystallization.

Step 6—Preparation of a Compound of Formula (9)

The compounds of formula (9) can be made by combining compounds offormulas (6) and (8) or combining compounds of formulas (7) and (8) bymethods known in the art. Compounds of formula (8) are commerciallyavailable or can be made by methods known in the art. A compound offormula (8) can be mixed with either compounds of formula (6) or (7) inthe presence of a base such as sodium hydride in a suitable solvent suchas NMP or DMA. After stirring at a temperature between room temperatureand 100° C. for between 1 h and 24 h or until reaction is complete, thereaction can be added to water and treated with acid such as 10% citricacid. The compound of formula (7) may be obtained by filtration orprecipitation.

Step 7—Preparation of a Compound of Formula (12)

The compounds of formula (12) can be made by combining compounds offormulas (10) and (11) by methods known in the art. Compounds offormulas (10) and (11) are commercially available or can be made bymethods known in the art. Compounds of formulas (10) and (11) can bemixed in the presence of a base such as potassium carbonate in asuitable solvent such as DMF. After stirring at a temperature betweenroom temperature and 50° C. for between 1 h and 24 h or until reactionis complete, the reaction is cooled to room temperature. To extract thecompound of formula (12), an organic solvent such as ethyl acetate maybe added, followed by washing with water and brine. The organic phasecan be concentrated to obtain the compound of formula (12). The compoundof formula (12) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation, orcrystallization.

Step 8—Preparation of a Compound of Formula (13)

The compounds of formula (13) may be prepared by reductive amination ofthe compounds of formula (12) by methods known in the art. Compounds offormula (12) and amines, that are commercially available or synthesizedby methods known in the art, can be mixed with a reducing agent such assodium triacetoxy borohydride or sodium cyanoborohydride in the presenceof acid, such as acetic acid, or Lewis acid, such as zinc chloride, in asuitable solvent such as dichloroethane or methanol. After stirring at atemperature between 0° C. and room temperature for between 1 h and 24 hor until reaction is complete, the reaction may be added to aqueoussolution such as saturated aqueous sodium bicarbonate solution. Toextract the compound of formula (13), an organic solvent such asmethylene chloride may be added, followed by washing with water andbrine. The organic phase can be concentrated to obtain the compound offormula (13). The compound of formula (13) may be purified by anysuitable methods known in the art such as chromatography on silica gel,trituration, precipitation, or crystallization.

Step 9—Preparation of a Compound of Formula (I)

The compounds of formula (I) can be made by combining the compounds offormula (9) and compounds of formula (13) by methods known in the art.Compounds of formulas (9) and (13) can be mixed in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium and a base suchas cesium carbonate, sodium carbonate, or potassium phosphate tribasicin a suitable solvent such as a mixture of dimethoxyethane and water, ora mixture of DMAc and water. After stirring at a temperature between 50°C. and 150° C. for between 1 and 24 hours, the reaction is allowed tocool to room temperature. Compounds of formula (I) may be filtered andconcentrated under reduced pressure. To extract the compound of formula(I), an organic solvent such as methylene chloride may be added,followed by washing with water and brine. The organic phase can beconcentrated to obtain the compound of formula (I). The compound offormula (I) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, reverse phase chromatography,trituration, precipitation, or crystallization.

Reaction Scheme II

The compounds of formula (I) may be prepared using the alternate methodssimilar to the Reaction Scheme II shown below.

Step 1—Preparation of a Compound of Formula (14)

The compounds of formula (14) can be made by combining the compounds offormulas (6) and (13) by methods known in the art. Compounds of formulas(9) and (13) can be mixed in the presence of a catalyst such astetrakis(triphenylphosphine)palladium and a base such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic in asuitable solvent such as a mixture of dimethoxyethane and water, or amixture of DMAc and water. After stirring at a temperature between 50°C. and 150° C. for between 1 and 24 hours, the reaction is allowed tocool to room temperature. Compounds of formula (14) may be filtered andconcentrated under reduced pressure. To extract the compound of formula(14), an organic solvent such as methylene chloride may be added,followed by washing with water and brine. The organic phase can beconcentrated to obtain the compound of formula (14). The compound offormula (14) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, reverse phase chromatography,trituration, precipitation, or crystallization.

Step 2—Preparation of a Compound of Formula (I)

The compounds of formula (I) can be made by combining the compounds offormulas (8) and (14) by methods known in the art. Compounds of formulas(8) and (14) can be mixed in the presence of a catalyst such astris(dibenzylideneacetone)dipalladium, a ligand such as xantphos, and abase such as cesium carbonate in a suitable solvent such as dioxane.After stirring at a temperature between 50° C. and 150° C. for between 1and 24 hours, the reaction is allowed to cool to room temperature.Compounds of formula (I) may be filtered and concentrated under reducedpressure. To extract the compound of formula (I), an organic solventsuch as methylene chloride may be added, followed by washing with waterand brine. The organic phase can be concentrated to obtain the compoundof formula (I). The compound of formula (I) may be purified by anysuitable methods known in the art such as chromatography on silica gel,reverse phase chromatography, trituration, precipitation, orcrystallization.

Reaction Scheme III

The compounds of formula (I) may be prepared using the alternate methodssimilar to the Reaction Scheme III shown below.

Step 1—Preparation of a Compound of Formula (15)

The compounds of formula (15) can be made by amination of compounds offormula (6) by methods known in the art. A compound of formula (6) canbe mixed with ammonium hydroxide solution in a suitable solvent such asN-methylpyrrolidone. After stirring at a temperature between 50° C. and150° C. for between 1 and 48 hours, the reaction is allowed to cool toroom temperature. Compounds of formula (15) may be added to water andfurther cooled to 0° C. while stirring. The compound of formula (15) maybe isolated by any suitable methods known in the art, such as filtrationor precipitation.

Step 2—Preparation of a Compound of Formula (16)

The compounds of formula (16) can be made by combining the compounds offormulas (13) and (15) by methods known in the art. Compounds of formula(13) and (15) can be mixed in the presence of a catalyst such astetrakis(triphenylphosphine)palladium and a base such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic in asuitable solvent such as a mixture of dimethoxyethane and water, amixture of dimethylacetamide and water, or a mixture ofdimethylformamide, dimethoxyethane, and water. After stirring at atemperature between 50° C. and 150° C. for between 1 and 24 hours, thereaction is allowed to cool to room temperature. Compounds of formula(16) may be filtered and concentrated under reduced pressure. To extractthe compound of formula (16), an organic solvent such as methylenechloride may be added, followed by washing with water and brine. Theorganic phase can be concentrated to obtain the compound of formula(16). The compound of formula (16) may be purified by any suitablemethods known in the art such as chromatography on silica gel, reversephase chromatography, trituration, precipitation, or crystallization.

Step 3—Preparation of a Compound of Formula (I)

The compounds of formula (I) can be made by combining the compounds offormulas (16) and (20) by methods known in the art. Compounds offormulas (16) and (20) can be mixed in the presence of a catalyst suchas tris(dibenzylideneacetone)dipalladium, a ligand such as xantphos, anda base such as cesium carbonate in a suitable solvent such as dioxane.After stirring at a temperature between 50° C. and 150° C. for between 1and 24 hours, the reaction is allowed to cool to room temperature.Compounds of formula (I) may be filtered and concentrated under reducedpressure. To extract the compound of formula (I), an organic solventsuch as methylene chloride may be added, followed by washing with waterand brine. The organic phase can be concentrated to obtain the compoundof formula (I). The compound of formula (I) may be purified by anysuitable methods known in the art such as chromatography on silica gel,reverse phase chromatography, trituration, precipitation, orcrystallization.

Reaction Scheme IV

The compounds of formula (I-B) may be prepared using the methods similarto the Reaction Scheme IV shown below.

Step 1—Preparation of a Compound of Formula (18)

The compounds of formula (18) can be made by removing thetert-butyloxycarbonyl protecting group of compounds of formula (17) bymethods known in the art. A compound of formula (17) can be mixed withan acidic solution such as 4M hydrochloric acid solution in a suitablesolvent such as dichloromethane or dioxane. After stirring at roomtemperature for between 10 minutes and 24 h, the solvent is evaporatedin vacuo. The compound of formula (18) may be isolated by any suitablemethods known in the art, such as filtration, trituration, orprecipitation.

Step 2—Preparation of a Compound of Formula (I-B)

The compounds of formula (I-B) can be made by reductive amination oramide synthesis of compounds of formula (18) by methods known in theart. Compounds of formula (18) can be mixed with amines, that arecommercially available or synthesized by methods known in the art, oracid chlorides, that are commercially available or synthesized bymethods known in the art, or carboxylic acids, that are commerciallyavailable or synthesized by methods known in the art, in the presence ofa reducing agent such as sodium triacetoxy borohydride or sodiumcyanoborohydride with an acid, such as acetic acid, or a Lewis acid,such as zinc chloride, in a suitable solvent such as dichloroethane ormethanol, or in the presence of a coupling reagent such as HATU orpropylphosphonic anhydride solution in a suitable solvent such asacetonitrile, dimethyl formide, and dichloroethane. After stirring at atemperature between 0° C. and 100° C. for between 1 h and 24 h, thereaction may be added to aqueous solution such as saturated aqueoussodium bicarbonate solution. To extract the compound of formula (I-B),an organic solvent such as ethyl acetate or methylene chloride may beadded, followed by washing with water and brine. The organic phase canbe concentrated to obtain the compound of formula (I-B). The compound offormula (I-B) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, trituration, precipitation, orcrystallization.

The compounds of formula (I) may be prepared using the alternate methodssimilar to the Reaction Scheme V shown below.

Reaction Scheme V

Step 1—Preparation of a Compound of Formula (19)

The compounds of formula (19) can be made by combining the compounds offormulas (9) and (12) by methods known in the art. Compounds of formulas(9) and (12) can be mixed in the presence of a catalyst such astetrakis(triphenylphosphine)palladium and a base such as cesiumcarbonate, sodium carbonate, or potassium phosphate tribasic in asuitable solvent such as a mixture of dimethoxyethane and water, amixture of dimethylacetamide and water, or a mixture of dimethylformide,dimethoxyethane, and water. After stirring at a temperature between 50°C. and 150° C. for between 1 and 24 hours, the reaction is allowed tocool to room temperature. Compounds of formula (19) may be filtered andconcentrated under reduced pressure. To extract the compound of formula(19), an organic solvent such as methylene chloride may be added,followed by washing with water and brine. The organic phase can beconcentrated to obtain the compound of formula (19). The compound offormula (19) may be purified by any suitable methods known in the artsuch as chromatography on silica gel, reverse phase chromatography,trituration, precipitation, or crystallization.

Step 2—Preparation of a compound of formula (I)

The compounds of formula (I) may be prepared by reductive amination ofthe compounds of formula (19) by methods known in the art. Compounds offormula (19) and amines, that are commercially available or synthesizedby methods known in the art, can be mixed with a reducing agent such assodium triacetoxy borohydride or sodium cyanoborohydride in the presenceof an acid, such as acetic acid, or a Lewis acid, such as zinc chloride,in a suitable solvent such as dichloroethane or methanol. After stirringat a temperature between 0° C. and room temperature for between 1 h and24 h or until reaction is complete, the reaction may be added to aqueoussolution such as saturated aqueous sodium bicarbonate solution. Toextract the compound of formula (I), an organic solvent such as ethylacetate and methylene chloride may be added, followed by washing withwater and brine. The organic phase can be concentrated to obtain thecompound of formula (I). The compound of formula (I) may be purified byany suitable methods known in the art such as chromatography on silicagel, trituration, precipitation, or crystallization.

VIII. Examples

Exemplary chemical entities of the present disclosure are provided inthe specific examples that follow. Those skilled in the art willrecognize that, to obtain the various compounds herein, startingmaterials may be suitably selected so that the ultimately desiredsubstituents will be carried through the reaction scheme with or withoutprotection as appropriate to yield the desired product. Alternatively,it may be necessary or desirable to employ, in the place of theultimately desired substituent, a suitable group that may be carriedthrough the reaction scheme and replaced as appropriate with the desiredsubstituent. Furthermore, one of skill in the art will recognize thatthe transformations shown in the schemes below may be performed in anyorder that is compatible with the functionality of the particularpendant groups.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

Procedure 1: Preparation of the compounds of formula (6) according toReaction Scheme I

A. Preparation of 2-bromo-5-(isopropylamino)-4-nitropyridine 1-oxide

In a multi-necked, round bottomed flask was placed2-bromo-5-fluoro-4-nitropyridine 1-oxide (1500.0 g, 6.3 mol) in THE (1.5L) and cooled to 0° C. To this was added isopropyl amine (600.0 mL, 7.0mol) drop wise at 0° C. over a period of 30 min. Reaction mixture wasslowly warmed to room temperature and stirred for 24 h. Then, thereaction mixture was filtered, washed with THE to give2-bromo-5-(isopropylamino)-4-nitropyridine 1-oxide which was used in thenext step without further purification.

B. Preparation of 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine

In toluene (21 L) was placed 2-bromo-5-(isopropylamino)-4-nitropyridine1-oxide (1400.0 g, 5.1 mol). To this was added triethylamine (4.2 L)slowly dropwise at room temperature over a period of 30 min and stirredfor 10 min. Then the reaction mixture was cooled to 0° C. followed bythe dropwise addition of POCl₃ (1.4 L) over a period of 30 min. Reactionmixture was slowly warmed to room temperature and heated to 65° C. for4h. Then, it was cooled to room temperature, poured into ice water andextracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃ solution, followed by brine solution, dried over sodiumsulfate and concentrated under reduced pressure. The crude mixture waspurified by column chromatography using 100-200 mesh silica gel and thecolumn was gradually eluted with 10% ethyl acetate in petroleum ether togive 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine.

C. Preparation of 6-bromo-2-chloro-N3-isopropylpyridine-3,4-diamine

To a solution of 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine(1000.0 g, 3.4 mol) in THF/MeOH (20 L/20 L) was added Zinc dust (1775.0g, 27.2 mol) followed by the dropwise addition of a solution of NH₄Cl(1816.0 g, 34.0 mol) in water (20 L) at room temperature and theresulting reaction mixture was stirred at room temperature for 1h. Then,the reaction mixture was diluted with ethyl acetate and filtered throughcelite bed. The filtrate was extracted with ethyl acetate and theorganic layer was dried with anhydrous sodium sulfate and concentratedunder reduced pressure. The crude compound was purified by washing withmethyl t-butyl ether to afford6-bromo-2-chloro-N3-isopropylpyridine-3,4-diamine.

D. Preparation of 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine

To a solution of 6-bromo-2-chloro-N3-isopropylpyridine-3,4-diamine(800.0 g, 3.0 mol) in CH(OCH₃)₃(5.2 L) was added HCOOH (65 mL). Afterthe reaction mixture was stirred at 70° C. for 3 h, the remainingsolvent was removed via distillation. Then water was added and theresulting mixture was extracted with CH₂Cl₂. The combined organic layerswere dried over anhydrous Na₂SO₄, concentrated, and purified by washingwith methyl t-butyl ether to give6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine.

The following compounds were prepared using a similar procedure exceptcommercially available amines including, ethylamine, cyclo-propylamine,and (S)-butylamine, were used instead of isopropylamine:

6-bromo-4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridine

6-bromo-4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridine

(S)-6-bromo-3-(sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridine Procedure2: Preparation of the Compounds of Formula (7) According to ReactionScheme I

A. Preparation of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine

A mixture of 6-bromo-3-isopropyl-4-chloro-3H-imidazo[4,5-c]pyridine (148g, 0.54 mol) and cesium fluoride (819 g, 5.40 mol) in DMF (1.2 L) washeated at 110° C. for 24 h. Reaction mixture was poured into ice water(1 L). The aqueous layer was extracted with ethyl acetate (3×1 L). Theorganic layers were dried over sodium sulfate and concentrated and thecrude mixture was further purified using column chromatography(EA/Hex=2:3-1:1) to yield6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 1 were used instead of6-bromo-3-isopropyl-4-chloro-3H-imidazo[4,5-c]pyridine (a skilledartisan will readily recognize without undue experimentation whichcompounds of Procedure 1 were used to prepare the below compounds):

6-bromo-3-ethyl-4-fluoro-3H-imidazo[4,5-c]pyridine

6-bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine

(S)-6-bromo-3-(sec-butyl)-4-fluoro-3H-imidazo[4,5-c]pyridine Procedure3: Preparation of the Compounds of Formula (9) According to ReactionScheme I

A. Preparation of6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-aminefrom 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine

To a solution of 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine(50.0 g, 182.0 mmol) and 3-fluoropyridin-4-amine (22.5 g, 200.0 mmol) inNMP (300 mL) was slowly added sodium hydride (11.7 g, 291.0 mmol) at 0°C. The mixture was stirred at 0° C. for 30 min and heated at 60° C. for16 h. Then, it was cooled to RT, quenched with water, and acidified topH 5 with 10% citric acid. The resulting precipitates were filtered anddried to afford6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

Procedure 4: Alternate Method to Prepare the Compounds of Formula (9)According to Reaction Scheme I

A. Preparation of6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-aminefrom 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine

To a solution of 3-fluoropyridin-4-amine (2.0 g, 18 mmol) in DMA (40 mL)was added sodium hydride (1.4 g, 36 mmol) over a period of 5 minutes.The mixture was stirred at room temperature for 15 minutes followed bythe addition of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine(5.5 g, 21 mmol). After stirring at room temperature for 16 hours, thereaction mixture was quenched with water (200 mL). The slurry wasstirred for 1 hour, filtered, and washed with water to give6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   commercially available amines, including        4-amino-5-fluoro-2-methylpyridine, 3,5-difluoropyridin-4-amine,        and 2-chloro-5-fluoropyridin-4-amine were used instead of        3-fluoropyridin-4-amine; and/or    -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine or the        compounds listed under Procedure 2 were used instead of        6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (a        skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 2 were used to        prepare the below compounds):

6-bromo-N-(5-fluoro-2-methylpyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine

6-bromo-N-(2-chloro-5-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine

6-bromo-3-ethyl-N-(3-fluoropyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-amine

6-bromo-N-(3,5-difluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine

(S)-6-bromo-3-(sec-butyl)-N-(3-fluoropyridin-4-yl)-3H-imidazo[4,5-c]pyridin-4-amine

Procedure 5: Preparation of the compounds of formula (13) according toReaction Scheme I

A. Preparation of3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

A mixture of 6-bromo-3,3-dimethylindolin-2-one (150 g, 625 mmol,commercially available), bis(pinacolato)diboron (206 g, 812 mmol),Pd(dppf)Cl₂/CH₂Cl₂ (45 g, 62.5 mmol) and potassium acetate (184 g, 1875mmol) in dimethyl sulfoxide (2000 mL) was stirred at 100° C. under Arfor 3h. The reaction was diluted with H₂O (10 L) and extracted withethyl acetate (4 L). The organic phase was washed with water followed bybrine, dried over Na₂SO₄, and purified by silica gel column (PE/EA=10:1)to give3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

B. Preparation of3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a mixture of3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(200 g, 696 mmol) and K₂CO₃ (240 g, 1740 mmol) in DMF (2 L) was added3-bromocyclobutanone (160 g, 1356 mmol). After the mixture was stirredat 50° C. under Ar for 2.5 h, it was cooled to room temperature, dilutedwith EtOAc, and filtered to remove solids. The filtrate was diluted withadditional EtOAc and water. The aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated, and purified by flash chromatography on silicagel (PE/EA=20:1) to give3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

C. Preparation of3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a solution of3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(7.0 g, 19.7 mmol) in dichloroethane (130 mL) was added piperidine (3.4g, 39.4 mmol) and acetic acid (3.6 g, 59.1 mmol). The reaction wascooled to 0° C. in an ice-bath and sodium triacetoxy borohydride (6.26g, 29.56 mmol) was added portion-wise. After completion of addition, thereaction was brought out of the ice bath and stirred at room temperaturefor 2 h. Then, the reaction mixture was quenched with saturated aqueoussodium bicarbonate solution and extracted with methylene chloride (3×200mL). The combined organic layers were washed with sat. NaHCO₃, brine,dried over sodium sulfate, filtered, and concentrated in vacuo to give3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure exceptthe amines indicated below were used instead of piperidine:

5-Azaspiro[2.4]heptane was used to prepare1-((1s,3s)-3-(5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indolin-2-one

(3S,4R)-3,4-Dimethylpyrrolidine was used to prepare1-((1S,3s)-3-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

2-Azabicyclo[2.2.2]octane was used to prepare1-((1s,3s)-3-(2-azabicyclo[2.2.2]octan-2-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

Azepane was used to prepare1-((1s,3s)-3-(azepan-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

6,6-Dimethyl-3-azabicyclo[3.1.0]hexane was used to prepare1-((1s,3s)-3-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

3-Azabicyclo[3.1.0]hexane was used to1-((1s,3s)-3-(3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

3-Azabicyclo[3.2.1]octane was used to prepare1-((1s,3s)-3-(3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

Piperidine-2,2,3,3,4,4,5,5,6,6-d10 was used to prepare3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl-d10)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

2-Fluoro-2-methylpropan-1-amine was used to prepare1-((1s,3s)-3-((2-fluoro-2-methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

(1S,4R)-2-Azabicyclo[2.2.1]heptane was used to prepare1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

(1R,4S)-2-Azabicyclo[2.2.1]heptane was used to prepare1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

1-Amino-2-methylpropan-2-ol was used to prepare1-((1s,3s)-3-((2-hydroxy-2-methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

3,3-dimethylpiperidine was used to prepare1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

2-Methylpropan-1-amine was used to prepare1-((1s,3s)-3-(isobutylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

3,3-Dimethylazetidine was used to prepare1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

Procedure 6: Preparation of the compounds of formula (13) according toReaction Scheme I

A. Preparation of3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

To a stirring solution of6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4 g,16.59 mmol) in dioxane (100 ml) were added bis(pinacolato)diboron (12.64g, 49.77 mmol), potassium acetate (4.88 g, 49.77 mmol), andPd(dppf)Cl₂/DCM (1354.92 mg, 1.66 mmol). The reaction mixture wasdegassed with N₂ for 5 min, sealed, and heated at 100° C. for 15 h. Thereaction mixture was cooled to room temperature, and then filteredthrough a pad of celite. The filtrate was diluted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andthen concentrated to give3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onewhich was used in the next step without further purification.

B. Preparation of(3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid

To a stirring solution3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one(1.1 g, 3.82 mmol) in NMP (20 ml) were added 3-bromocyclobutanone(1354.15 μl, 15.27 mmol) and K₂CO₃ (2.64 g, 19.09 mmol). The resultingmixture was heated at 50° C. for 15 h. The reaction mixture was cooledto room temperature and then diluted with EtOAc. The organic layer waswashed with water, brine, dried over Na₂SO₄, filtered, then concentratedto give(3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid, which was used in the next step without further purification.

C. Preparation of(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid

To a stirring solution of(3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid (2 g, 5.61 mmol) in DCE (30 ml) were added piperidine (1.11 ml,11.2 mmol), Na(OAc)₃BH (1.78 g, 8.42 mmol), and AcOH (0.97 ml, 16.8mmol) at room temperature. The resulting mixture was stirred for 2 hthen quenched with satd. NaHCO₃. Aqueous layer was extracted with DCMand the combined organic layer was dried over Na₂SO₄, then concentratedto give(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)boronicacid, which was used in the next step without further purification.

Procedure 7: Preparation of the compounds of formula (13) according toReaction Scheme I

A. Preparation of3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

To a stirring solution of 6-bromo-3-hydroxy-3-methylindolin-2-one (4 g,16.5 mmol) in dioxane (80 ml) were added bis(pinacolato)diboron (8.4 g,33 mmol), potassium acetate (3.2 g, 33 mmol), and Pd(dppf)Cl₂-DCM (1.4g, 1.65 mmol). The nitrogen gas was bubbled through the resultingsuspension for 3 min then heated over night at 90° C. After cooling toroom temperature, the reaction mixture was filtered and the filter cakewas washed with EtOAc then concentrated in vacuo. The crude product waspurified by silica gel chromatography (Hexanes/EtOAc) to afford3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

B. Preparation of3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a stirring solution of3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-onein NMP (100 mL) were added 3-bromocyclobutanone (5.53 ml, 62.4 mmol) andpotassium carbonate (325 mesh, 10.8 g, 78 mmol). The resultingsuspension was stirred at 50° C. for overnight. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (100 ml) andthe organic layer was washed with water (100 ml), brine (100 ml), driedover Na₂SO₄, concentrated, and purified by flash chromatography(Hexanes/EtOAc) to afford3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

C. Preparation of3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

To a solution of3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(3.0 g, 8.4 mmol) in dichloroethane (60 mL) was added piperidine (1.4 g,16.8 mmol), acetic acid (1.5 mL, 25.2 mmol), and sodium triacetoxyborohydride (2.7 g, 12.6 mmol). After stirring at room temperature for 5h, the reaction mixture was quenched with saturated aqueous sodiumbicarbonate solution and extracted with methylene chloride (3×200 mL).The combined organic layers were washed with sat. NaHCO₃, brine, driedover sodium sulfate, filtered, and concentrated in vacuo to give3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one,which was used in the next step without purification.

Procedure 8: Preparation of the Compounds of Formula (17) According toReaction Scheme

A. Preparation of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a mixture of tert-butyl2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(0.81 g, 1.89 mmol), which may be prepared following the literatureprocedure (intermediate 7.33 in WO2015017610A1, also published asUS20150038488A1), and powdered potassium carbonate (0.65 g of 325 mesh,4.73 mmol) in DMF (7.5 mL) was added 3-bromocyclobutanone (0.21 mL, 2.53mmol). After the mixture was heated to 50° C. for 1 h, it was cooled toroom temperature and filtered to remove potassium carbonate. Thefiltrate was diluted with EtOAc and water, and extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄),filtered, concentrated, and purified via flash chromatography on silicagel with gradient elution (0-100% EtOAc/hexanes) to give tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a mixture of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(0.5 g, 1.0 mmol) in DCE (10 mL) was added piperidine (0.3 mL, 3.0mmol), AcOH (0.2 mL, 3.0 mmol), and sodium triacetoxyborohydride (320mg, 1.5 mmol). After stirring at room temperature for 16 h, the reactionmixture was diluted with sat. NaHCO₃ and DCM and stirred vigorously for5 min. The organic layer was separated, dried over Na₂SO₄, andconcentrated under reduced pressure to give tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

The following compounds were prepared using a similar procedure exceptthe amines indicated below were used instead of piperidine:

3,3-Dimethylpyrrolidine was used to prepare tert-butyl1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

5-Azaspiro[2.4]heptane was used to prepare tert-butyl1-((1s,3s)-3-(5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3,3-Dimethylpiperidine was used to prepare tert-butyl1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

5-Azaspiro[2.5]octane was used to prepare tert-butyl1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(1R,5S)-3-Azabicyclo[3.2.0]heptane was used to prepare tert-butyl1-((1S,3s)-3-((1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(3R,4S)-3,4-Dimethylpyrrolidine was used to prepare tert-butyl1-((1S,3s)-3-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(1R,4S)-2-azabicyclo[2.2.1]heptane was used to prepare tert-butyl1-((1R,3s)-3-((2S,5R)-2,5-dimethylpiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3-Azabicyclo[3.2.1]octane was used to prepare tert-butyl1-((1s,3s)-3-(3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3-Oxa-8-azabicyclo[3.2.1]octane was used to prepare tert-butyl1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3-Azabicyclo[3.1.1]heptane was used to prepare tert-butyl1-((1s,3s)-3-(3-azabicyclo[3.1.1]heptan-3-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(R)-3-Methylpiperidine was used to prepare tert-butyl1-((1S,3s)-3-((R)-3-methylpiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

8-Oxa-3-azabicyclo[3.2.1]octane was used to prepare tert-butyl1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(S)-(4,4-Dimethylpyrrolidin-2-yl)methanol was used to prepare tert-butyl1-((1R,3s)-3-((S)-2-(hydroxymethyl)-4,4-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(R)-(4,4-Dimethylpyrrolidin-2-yl)methanol was used to prepare tert-butyl1-((1S,3s)-3-((R)-2-(hydroxymethyl)-4,4-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(S)-4,4-Dimethylpyrrolidin-3-ol was used to prepare tert-butyl1-((1R,3s)-3-((S)-4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

4,4-Dimethylpyrrolidin-3-ol was used to prepare tert-butyl1-((s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1-carboxylate

(R)-3-fluoropyrrolidine was used to prepare tert-butyl1-((1S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(R)-3-Methylpyrrolidine was used to prepare tert-butyl1-((1S,3s)-3-((R)-3-methylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(S)-3-Fluoropyrrolidine was used to prepare tert-butyl1-((1R,3s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

(S)-3-Methylpyrrolidine was used to prepare tert-butyl1-((1R,3s)-3-((S)-3-methylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3-(Difluoromethyl)pyrrolidine was used to prepare tert-butyl1-((1s,3s)-3-(3-(difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

7-Fluoro-5-azaspiro[2.4]heptane was used to prepare tert-butyl1-((1s,3s)-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

4-Fluoropiperidine was used to prepare tert-butyl1-((1s,3s)-3-(4-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3,3-dimethylazetidine was used to prepare tert-butyl1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

C. Preparation of tert-butyl1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a solution of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(250 mg, 0.5 mmol) in MeOH (6 mL) was added (R)-3-fluoropiperidinehydrochloride (211 mg, 1.5 mmol), Zinc chloride (103 mg, 0.76 mmol), andsodium cyanoborohydride (95 mg, 1.5 mmol). After stirring overnight atroom temperature, the reaction was diluted with sat. NaHCO₃ and DCM andstirred vigorously for five minutes. Then the organic layer wasseparated, dried (Na₂SO₄), and concentrated to give tert-butyl1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

The following compounds were prepared using a similar procedure exceptthe amines indicated below were used instead of (R)-3-fluoropiperidinehydrochloride:

3-Fluoro-3-methylpiperidine was used to prepare tert-butyl1-((1s,3s)-3-(3-fluoro-3-methylpiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

3-Fluoro-3-methylpyrrolidine was used to prepare tert-butyl1-((1s,3s)-3-(3-fluoro-3-methylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

Procedure 9: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a solution of tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(2.27 g, 4.01 mmol) in dioxane (20 mL) was added 4M hydrochloric acidsolution (19.07 ml). The mixture was stirred at room temperature for 10min, at which point LC-MS indicated complete conversion. The mixture wasconcentrated and the trace amounts of acid were chased off on therotovap using methanol three times. The residue was dissolved in minimalDCM, and then crashed out with ether and hexanes. The precipitates werefiltered and washed with hexanes to provide1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 8 were used instead of tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(a skilled artisan will readily recognize without undue experimentationwhich compounds of Procedure 8 were used to prepare the belowcompounds):

1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-azabicyclo[3.1.1]heptan-3-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((3S,4R)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-3-methylpiperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3r)-3-((S)-2-(hydroxymethyl)-4,4-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-2-(hydroxymethyl)-4,4-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1R,3s)-3-((S)-4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-3-methylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1R,3s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(4-fluoropiperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1R,3s)-3-((S)-3-methylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-(difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-oneProcedure 10: Preparation of the Compounds of Formula (13) According toReaction Scheme 0

A. Preparation of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

To a stirring solution of6-bromo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one (4 g,16.5 mmol) in DMSO (1160 ml) were added bis(pinacolato)diboron (20.1 g,24.7 mmol), potassium acetate (80.7 g, 822 mmol), and Pd(dppf)Cl₂ (20.1g, 24.7 mmol). The nitrogen gas was bubbled through the resultingsuspension for 5 min and then the suspension was heated at 90° C. for 6h. After cooling to room temperature, the reaction mixture was dilutedwith EtOAc and washed with brine. The organic layer was dried (Na₂SO₄),filtered, concentrated, triturated with petroleum ether/EtOAc, andfiltered to give6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one.

B. Preparation of1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

To a stirring solution of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one(67.0 g, 203 mmol) in DMF (500 mL) was added potassium carbonate (70.3g, 509 mmol). After stirring at 50° C. for 4 h, 3-bromocyclobutanone(60.6 g, 407 mmol) was added to the mixture. The resulting suspensionwas stirred at 50° C. for 1 h. After cooling to room temperature, thereaction mixture was filtered, concentrated, and purified by flashchromatography (Petroleum ether/EtOAc) to afford1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one.

C. Preparation of1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

To a solution of1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one(3.0 g, 8.4 mmol) in dichloroethane (30 mL) was added3,3-dimethylpyrrolidine (1.5 g, 15.1 mmol), acetic acid (1.4 mL, 22.7mmol), and sodium triacetoxy borohydride (2.4 g, 11.3 mmol). Afterstirring at room temperature for 48 h, the reaction mixture was quenchedwith saturated aqueous sodium bicarbonate solution and extracted withmethylene chloride. The combined organic layers were washed with sat.NaHCO₃, brine, dried over sodium sulfate, filtered, and concentrated invacuo to give1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one,which was used in the next step without purification.

Procedure 11: Preparation of the Compounds of Formula (I-B) According toReaction Scheme IV

A. Preparation of1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(1810 mg, 3.89 mmol) and triethylamine (5.42 ml, 38.89 mmol) indichloromethane (8 ml) was added acetic anhydride (0.55 ml, 5.83 mmol).The mixture was stirred at room temperature for 1 h, then diluted withDCM and water, and extracted with DCM. The combined organic layers werewashed with brine and concentrated to provide1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 9 were used instead of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

1′-Acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1′-Acetyl-1-((1S,3s)-3-((R)-3-methylpiperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1′-Acetyl-1-((1S,3s)-3-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-1′-acetyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-oneB. Preparation of1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

In a 20 mL vial were placed1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(300 mg, 0.6 mmol), 4-methyltetrahydro-2H-pyran-4-carboxylic acid (0.25ml, 1.2 mmol), HATU (454.27 mg, 0.8 mmol), and N,N-Diisopropylethylamine(0.21 ml, 1.2 mmol) in ACN (5 ml). The mixture was stirred at RT for 16h, then quenched with saturated NaHCO₃, and extracted with DCM. Thecombined organic layers were washed with water and brine, dried(Na₂SO₄), and concentrated to afford1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the carboxylic acids indicated below were used instead of        4-methyltetrahydro-2H-pyran-4-carboxylic acid; and/or    -   the compounds listed under Procedure 9 were used instead of        1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 9 were used to        prepare the below compounds):

(S)-2-Hydroxypropanoic acid was used to prepare1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(R)-2-Hydroxypropanoic acid was used to prepare1′-((S)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Hydroxy-2,2-dimethylpropanoic acid was used to prepare1′-(3-hydroxy-2,2-dimethylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

2-Hydroxy-2-methylpropanoic acid was used to prepare1′-(2-hydroxy-2-methylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare1′-(3-methyloxetane-3-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

2-Hydroxy-2-methylpropanoic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(2-hydroxy-2-methylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare1-((1s,3s)-3-(5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-1′-(3-methyloxetane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-1′-(3-methyloxetane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare1-((1s,3s)-3-(3-azabicyclo[3.1.1]heptan-3-yl)cyclobutyl)-1′-(3-methyloxetane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare11-((1S,3s)-3-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(3-methyloxetane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1′-(3-methyloxetane-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(S)-Tetrahydrofuran-2-carboxylic acid was used to prepare1-((1S,3R)-3-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((S)-tetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Hydroxy-2,2-dimethylpropanoic acid was used to prepare1-((1S,3s)-3-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(3-hydroxy-2,2-dimethylpropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(S)-2-Hydroxypropanoic acid was used to prepare1-((1s,3S)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1′-((R)-2-hydroxypropanoyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

2-Methyloxetane-2-carboxylic acid was used to prepare1′-(2-methyloxetane-2-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

2-Methyloxetane-2-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(2-methyloxetane-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(S)-Tetrahydrofuran-2-carboxylic acid was used to prepare1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((S)-tetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(R)-Tetrahydrofuran-2-carboxylic acid was used to prepare1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((R)-tetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

2-Methyltetrahydrofuran-2-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(2-methyltetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(S)-Tetrahydrofuran-3-carboxylic acid was used to prepare1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((S)-tetrahydrofuran-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(R)-Tetrahydrofuran-3-carboxylic acid1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((R)-tetrahydrofuran-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

3-Methyltetrahydrofuran-3-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(3-methyltetrahydrofuran-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(+)-Cis-3-Methyltetrahydrofuran-2-carboxylic acid was used to prepare amixture of1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((2R,3S)-3-methyltetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-oneand1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((2S,3R)-3-methyltetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

(+)-Cis-5-methyltetrahydrofuran-2-carboxylic acid was used to prepare amixture of1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((2R,5R)-5-methyltetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-oneand1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-((2S,5S)-5-methyltetrahydrofuran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

2-(Oxetan-3-yl)acetic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(2-(oxetan-3-yl)acetyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

Oxetane-2-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetane-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

Oxetane-2-carboxylic acid was used to prepare1′-(oxetane-2-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

Tetrahydro-2H-pyran-4-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(tetrahydro-2H-pyran-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

Tetrahydro-2H-pyran-2-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(tetrahydro-2H-pyran-2-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

Tetrahydro-2H-pyran-3-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(tetrahydro-2H-pyran-3-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

4-Methyltetrahydro-2H-pyran-4-carboxylic acid was used to prepare1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

C. Preparation of1′-(1-methylcyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(0.3 g, 0.6 mmol) in DMF (3 mL) was added1-methylcyclopropane-1-carboxylic acid (0.12 g, 1.2 mmol), DIEA (1.04mL, 5.97 mmol) followed by a 50% solution of propylphosphonic anhydride(T3P) in EtOAc, (0.31 mL, 0.53 mmol) and the mixture was stirred at roomtemperature for 72 hours. The mixture was then quenched with water andextracted twice with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), concentrated to give1′-(1-methylcyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the carboxylic acids indicated below were used instead of        1-methylcyclopropane-1-carboxylic acid; and/or    -   the compounds listed under Procedure 9 were used instead of        1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 9 were used to        prepare the below compounds):

3-Fluorobicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare1′-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

D. Preparation of methyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(0.3 g, 0.6 mmol) in DCM (5 mL) was added DIEA (1.0 mL, 5.6 mmol) andmethyl carbonochloridate (0.1 g, 1.1 mmol). After the mixture wasstirred at room temperature for 2 h, it was quenched with water andextracted with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), and concentrated to give methyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate,which was used in the next step without purification.

E. Preparation of1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-onehydrochloride (1.50 g, 2.79 mmol) and 3-oxetanone (0.49 mL, 0.60 g, 8.4mmol) in methanol (28 mL) was added zinc chloride (570 mg, 4.18 mmol),followed by sodium cyanoborohydride (525 mg, 8.36 mmol). The mixture wassealed and heated to 40° C. with stirring for 2 h. After the reactionmixture was cooled, saturated aqueous sodium bicarbonate was added, andthe resulting mixture was extracted three times with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under vacuum. The resulting residue was dissolved in EtOAc,washed once more with saturated aqueous sodium bicarbonate, dried oversodium sulfate, filtered, and concentrated under vacuum to afford1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one,which was used in the next step without purification.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedure 9 were used instead of1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

1-((1R,3s)-3-((S)-2-(hydroxymethyl)-4,4-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-2-(hydroxymethyl)-4,4-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1R,3s)-3-((S)-4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-3-methylpiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(4-fluoropiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((R)-3-methylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1R,3s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1R,3s)-3-((S)-3-methylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-(difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-oneProcedure 12: Preparation of the Compounds of Formula I According toReaction Scheme I

A. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 1)

In a microwave reaction vial were placed6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine(350.0 mg, 1.0 mmol),1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(591.3 mg, 1.0 mmol), Pd(PPh₃)₄(57.7 mg, 0.05 mmol), and Cesiumcarbonate 99.95% (976.9 mg, 3.0 mmol) in DME/H₂O (3 mL/1 mL). Themixture was sonicated and degassed for 15 sec, placed in the microwavereactor, and heated at 125° C. for 15 min. Then the mixture was purifiedby flash chromatography (100% DCM to 50% MeOH in DCM) and reverse phasechromatography to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(167 mg, 23% yield). ES/MS m/z=735.5 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ10.64 (s, 1H), 9.65 (s, 1H), 9.05-8.65 (m, 2H), 8.50-8.24 (m, 2H),7.87-7.38 (m, 4H), 5.14 (p, J=6.7 Hz, 1H), 4.48-4.13 (m, 1H), 3.92 (t,J=5.7 Hz, 4H), 3.75-3.23 (m, 8H), 3.03-2.69 (m, 6H), 2.21-0.97 (m, 23H).

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 3 and 4 were used instead        of        6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 3 and 4 were used        to prepare the below compounds); and/or    -   the compounds listed under Procedure 11 were used instead of        1′-(4-methyltetrahydro-2H-pyran-4-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 11 were used to        prepare the below compounds):

Ex- ample Structure #

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19A and 19B

20A and 20B

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

B. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one(Example 37)

A suspension of6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine(190.0 mg, 0.5 mmol),1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(300.0 mg, 0.5 mmol), and tetrakis(triphenylphosphine)palladium (63.0mg, 0.05 mmol) in a 1:1 mixture of DME/DMF (6 mL) was treated with 2Maqueous Na₂CO3 (0.42 mL, 0.8 mmol). The mixture was sparged with N₂ for30 seconds, then sealed and stirred at 130° C. under microwaveirradiation for 30 min. The reaction mixture was cooled to roomtemperature, diluted with water, and extracted three times with 3:1DCM/MeOH. The combined organic layers were concentrated under vacuum,and the resulting crude residue was purified via flash chromatography onsilica gel with gradient elution (0-100% EtOAc/hexanes followed by0-100% MeOH/DCM). Product-containing fractions were combined,concentrated under vacuum, and further purified via reverse phasepreparative HPLC to afford6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 3 and 4 were used instead        of        6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 3 and 4 were used        to prepare the below compounds); and/or    -   the compounds listed under Procedures 6 and 11 were used instead        of        1-((1s,3s)-3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 11 were used to        prepare the below compounds):

Structure Example #

38

39

40

41

42

43

44

45

46

47

48

49

50

51

C. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-((2-hydroxy-2-methylpropyl)amino)cyclobutyl)-3,3-dimethylindolin-2-one(Example 52)

To a mixture of6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine(98 mg, 0.28 mmol, 1.2 equiv),1-((1s,3s)-3-((2-hydroxy-2-methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(100 mg, 0.23 mmol, 1.0 equiv), Pd(PPh₃)₄(27 mg, 0.023 mmol, 10 mol %)and K₃PO₄ (149 mg, 0.70 mmol, 3 equiv) was added degassed DMAc (2.0 mL)and water (0.4 mL). The reaction was stirred in a sealed vessel at 90°C. for 3 hours. The reaction mixture was subsequently diluted with EtOAcand water, extracted twice with EtOAc and the combined organics weredried over MgSO₄, filtered, concentrated, and purified by reverse phaseHPLC (10-65% ACN/H₂O) to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-((2-hydroxy-2-methylpropyl)amino)cyclobutyl)-3,3-dimethylindolin-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 3 and 4 were used instead        of        6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 3 and 4 were used        to prepare the below compounds); and/or    -   the compounds listed under Procedures 5 and 7 were used instead        of        1-((1s,3s)-3-((2-hydroxy-2-methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 5 and 7 were used        to prepare the below compounds):

Structure Example #

53

54

55

56

57

58

59

60

61

62

63

64

65

66

Procedure 13: Preparation of the Compounds of Formula (14) According toReaction Scheme II

A. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

To a solution of3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one(1.0 g, 0.305 mmol) in DME (100 ml) were added6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (0.97 g, 3.53mmol), Pd(PPh₃)₄ (55 mg, 0.047 mmol), and 2M Na₂CO₃ (1.77 ml, 3.53mmol). The resulting mixture was degassed by bubbling argon gas throughfor 3 min and then the reaction vessel was sealed. After heating at 90°C. for 1 h, the reaction mixture was cooled then diluted with EtOAc. Theorganic layer was washed with water, brine, dried over Na₂SO₄,concentrated, and purified by flash chromatography (DCM/MeOH 50%) toafford6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (a        skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 1 were used to        prepare the below compounds); and/or    -   the compounds listed under Procedures 5, 8, and 10 were used        instead of        3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 5, 8, and 10 were        used to prepare the below compounds):

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(isobutylamino)cyclobutyl)-3,3-dimethylindolin-2-one

6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one

tert-butyl6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

tert-butyl6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylateProcedure 14: Preparation of the Compounds of Formula (14) According toReaction Scheme II

A. Preparation of1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

In a round bottomed flask were placed1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(0.8 g, 1.6 mmol),6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (866 mg, 3.2mmol), Pd(PPh₃)₄(91 mg, 0.08 mmol), and cesium carbonate (668 mg, 6.3mmol). To this mixture were added DME (10 mL) and water (3 mL) and theresulting mixture was heated to 120° C. for 1 h under nitrogenatmosphere. Then it was diluted with EtOAc and water, and extracted withEtOAc. The combined organic layers were concentrated under reducedpressure and purified by column chromatography (0-10% DCM/MeOH) to give1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 1 were used instead of        6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine    -   the compounds listed under Procedure 11 were used instead of        1′-acetyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

1′-acetyl-6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-oneProcedure 15: Preparation of the Compounds of Formula (I-B) According toReaction Scheme IV

A. Preparation of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

To a flask was charged tert-butyl1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(1.0 g, 1.7 mmol),6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (0.9 g, 3.4mmol), Pd(PPh₃)₄(0.2 g, 0.17 mmol), and cesium carbonate (2.0 g, 6.8mmol). DME (10 mL) and water (3 mL) were added and the reaction washeated to 120° C. for 1 h under nitrogen atmosphere. The reaction wasdiluted with EtOAc and water, and extracted with EtOAc. The combinedorganic layers were concentrated under reduced pressure and purified bycolumn chromatography (100% DCM to 10% MeOH/DCM) to give tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate(550 mg, 0.85 mmol) in dichloromethane (5 mL) was added 4N HCl indioxane (1 mL). After stirring at room temperature overnight, thereaction mixture was concentrated under reduced pressure to afford6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

C. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetane-3-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

In a flask was placed6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(82 mg, 0.14 mmol), oxetane-3-carboxylic acid (17 mg, 0.17 mmol), andDIPEA (0.70 ml, 0.12 mmol) in DMF (1 mL). To this mixture was added HATU(80 mg, 0.21 mmol). The mixture was stirred at room temperature for 1 h,then quenched with water and extracted with DCM. The combined organiclayers were washed with water and brine, dried (Na₂SO₄), concentrated,and purified by reverse phase HPLC to give6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetane-3-carbonyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe carboxylic acid indicated below was used instead ofoxetane-3-carboxylic acid:

3-Methyloxetane-3-carboxylic acid was used to prepare6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(3-methyloxetane-3-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

Oxetane-2-carboxylic acid was used to prepare6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetane-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

D. Preparation of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

To a flask charged with6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(460 mg, 0.84 mmol) and 3-oxetanone (182 mg, 2.5 mmol) in methanol (3mL) was added zinc chloride (172 mg, 1.3 mmol) followed by sodiumcyanoborohydride (159 mg, 2.5 mmol). The mixture was sealed and heatedto 40° C., stirred for 2 h., cooled, and then quenched with saturatedaqueous sodium bicarbonate. The aqueous layer was extracted three timeswith dichloromethane. The combined organic layers were dried over sodiumsulfate, filtered, concentrated under vacuum, and purified by reversephase HPLC to give6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 8 and 13 were used instead        of tert-butyl        1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 8 and 13 were used        to prepare the below compounds):

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3-fluoro-3-methylpiperidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3-fluoro-3-methylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-oneProcedure 16: Preparation of the Compounds of Formula I According toReaction Scheme II

A. Preparation of1′-acetyl-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 67)

In a microwave vial were placed1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(90 mg, 0.16 mmol), 3-fluoropyridin-4-amine (35 mg, 0.31 mmol),Pd₂(dba)₃ (8 mg, 0.02 mmol), Xantphos (8 mg, 0.02 mmol), and cesiumcarbonate (127 mg, 0.39 mmol) in Dioxane (3 mL). The vial was sonicated,purged with nitrogen gas, and heated to 150° C. for 30 minutes. Thereaction was filtered through a pad of celite with MeOH andconcentrated. The resulting crude product was purified by normal phasechromatography (0-20% MeOH/DCM) and reverse phase chromatography to give1′-acetyl-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 13, 14, and 15 were used        instead of        1′-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 13, 14, and 15        were used to prepare the below compounds); and/or    -   the optionally substituted amino pyridines, that are        commercially available or can be made by methods known in the        art, such as 2,6-difluoropyridin-3-amine,        3,5-difluoropyridin-2-amine,        4-amino-5-fluoro-N-isopropylpicolinamide, and        4-amino-5-fluoro-N-methylpicolinamide were used instead of        3-fluroropyrin-4-amine; or    -   the optionally substituted amino pyridones, that are        commercially available or can be made by methods known in the        art, such as 5-amino-1-methylpyridin-2(1H)-one and        5-aminopyridin-2(1H)-one were used instead of        3-fluoropyridin-4-amine; or    -   the compounds listed under Procedure 28 were used instead of        3-fluoropyridin-4-amine (a skilled artisan will readily        recognize without undue experimentation which compounds of        Procedure 28 were used to prepare the below compounds):

Structure Example #

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Procedure 17: Preparation of the Compounds of Formula (16) According toReaction Scheme III

A. Preparation of 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine

A 500 mL pressure vessel equipped with a magnetic stir bar was chargedwith 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (10.0 g,38.8 mmol) followed by N-methylpyrrolidone (100 mL). The resultingsolution was treated with ammonium hydroxide solution (28% NH3, 54 mL,390.0 mmol). The vessel was sealed, and the mixture stirred at 80° C. ina heating block for 48 h. The reaction mixture was then cooled to roomtemperature, carefully opened, and poured into 900 mL of water. Themixture was further cooled in an ice bath with stirring, then the crudeproduct was isolated by vacuum filtration and dried under a stream ofair to afford 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

B. Preparation of6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

A suspension of1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(736 mg, 1.41 mmol),6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine (300 mg, 1.18mmol), and tetrakis(triphenylphosphine)palladium (136 mg, 118 umol) in1:1 DMF/DME (12 mL) was treated with 2M aqueous Na₂CO₃ (4.1 mL, 8.2mmol). The mixture was sparged with N₂ for 1 min, then sealed andstirred vigorously at 120° C. overnight. The reaction mixture was cooledto room temperature, diluted with water, and extracted three times withEtOAc. The combined organic layers were concentrated under vacuum andpurified via flash chromatography on silica gel with gradient elution(0-100% EtOAc/hexanes followed by 0-100% MeOH/DCM) to afford6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedures 5, 7, and 11 were used instead of1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(a skilled artisan will readily recognize without undue experimentationwhich compounds of Procedures 5, 7, and 11 were used to prepare thebelow compounds):

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1′-(oxetan-3-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(3-methyloxetane-3-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

1′-acetyl-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

C. Preparation of6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

In a microwave vial were placed1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(130 mg, 0.242 mmol),6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine (62 mg, 0.242mmol), palladium tetrakis (28 mg, 0.024 mmol), and cesium carbonate (154mg, 0.726 mmol) in DMAc (2 mL) and water (0.4 mL). The mixture wasdegassed with N₂, sealed, and heated to 90° C. for 2 h., partitionedbetween EtOAc and water, and then extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered, concentrated in vacuo,and purified by flash chromatography (DCM/MeOH/NEt₃) to give6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compound was prepared using a similar procedure except1′-(3-hydroxy-2,2-dimethylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-onelisted under Procedure 11 was used instead of1′-((R)-2-hydroxypropanoyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one:

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(3-hydroxy-2,2-dimethylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

Procedure 18: Preparation of the compounds of Formula I according toReaction Scheme III

A. Preparation of6-(4-((2,3-difluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 91)

A suspension of6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(100 mg, 176 umol), 4-bromo-2,3-difluoropyridine (68 mg, 351 umol),Pd₂(dba)₃ (16 mg, 18 umol), Xantphos (18 mg, 35 umol), and Cs₂CO₃ (286mg, 878 umol) in 1,4-dioxane (3 mL) was sparged with argon for 30seconds. The reaction vial was then sealed and the mixture stirredvigorously at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature, diluted with EtOAc, and filtered through celite. Thefiltrate was concentrated under vacuum, and the resulting crude residuewas purified via flash chromatography on silica gel with gradientelution (0-100% EtOAc/hexanes followed by 0-100% MeOH/DCM).Product-containing fractions were combined, concentrated under vacuum,and further purified via reverse phase preparative HPLC to afford6-(4-((2,3-difluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 17 were used instead of        6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 17 were used to        prepare the below compounds); and/or    -   the optionally substituted fluoro pyridines, that are        commercially available or can be made by methods known in the        art, such as 4-bromo-2,5-difluoropyridine,        4-bromo-2,3-difluoropyridine5-bromo-4-fluoro-2-methoxypyridine,        (4-bromo-5-fluoropyridin-2-yl)methanol, 3-bromo-2,6-di        fluoropyridine, and 4-bromo-5-fluoro-N,N-dimethylpyridin-2-amine        were used instead of 4-bromo-2,3-difluoropyridine; or    -   the compounds listed under Procedure 29 were used instead of        4-bromo-2,3-difluoropyridine (a skilled artisan will readily        recognize without undue experimentation which compounds of        Procedure 29 were used to prepare the below compounds):

Structure Example #

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B. Preparation of1′-acetyl-6-(4-((7-fluoroisoquinolin-6-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 105)

A mixture of1′-acetyl-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(201 mg, 0.36 mmol), 6-bromo-7-fluoro-isoquinoline (163.52 mg, 0.72mmol), Xanthphos Pd G3 (68.6 mg, 0.07 mmol), and Cesium carbonate, 99.9%(589.23 mg, 1.81 mmol) in 1,4-dioxane (4 mL) was sparged with nitrogen.The reaction vial was placed in the microwave reactor and heated at 120°C. for 1 h. Then the reaction mixture was cooled to room temperature,suspended in 1 M K₂CO₃, extracted with DCM/MeOH, dried over Na₂SO₄,filtered through celite, and concentrated. The crude mixture waspurified by combiflash (100% DCM to 100% MeOH) followed by prep HPLC toafford1′-acetyl-6-(4-((7-fluoroisoquinolin-6-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

Procedure 19: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of tert-butyl6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate

To a mixture of6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine(1.5 g, 4.8 mmol) and tert-butyl2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(2.5 g, 4.5 mmol) were added DME (45 mL) and 2M Cs₂CO₃ (10.7 mL, 21.4mmol). Then the reaction mixture was de-gassed for a few mins followedby the addition of tetrakistriphenylphosphine palladium (0.5 g, 0.43mmol). The mixture was de-gassed again for ˜1 min then heated in an oilbath at 95° C. for 2 h. The reaction mixture, after cooling to roomtemperature, was filtered on a bed of celite with Na₂SO₄, concentrated,and purified by flash chromatography on silica gel with gradient elution(10% NH40H in MeOH/EtOAc/hexanes) to give tert-butyl6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of tert-butyl6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(2.3 g, 3.3 mmol) in DCM (28 mL) was drop wise added 4M HCl/dioxane (16mL, 65 mmol). The mixture was stirred at room temperature for 1 h. Thesolvent was evaporated in vacuo and the resulting residue was trituratedwith hexanes. After decanting the supernatant, the residual solvent wasconcentrated again to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one,which was used as is in the next step without further purification.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 3 and 4 were used instead        of        6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 3 and 4 were used        to prepare the below compounds); and/or    -   the compounds listed under Procedure 8 were used instead of        tert-butyl        2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 8 were used to        prepare the below compounds):

1-((1S,3s)-3-((1R,5S)-3-azabicyclo[3.2.0]heptan-3-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(3-ethyl-4-((3-fluoropyridin-4-yl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-((5-fluoro-2-methylpyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((5-fluoro-2-methylpyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

6-(4-((2-chloro-5-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-6-(4-((5-fluoro-2-methylpyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-oneProcedure 20: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

In a round bottomed flask were placed1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one(400 mg, 0.86 mmol),6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine(250 mg, 0.71 mmol), Pd(PPh₃)₄(57 mg, 0.05 mmol), and sodium carbonate(303 mg, 2.9 mmol) in DME (6 mL) and water (2 mL). The mixture waspurged with nitrogen gas, and heated to 100° C. overnight. The reactionwas filtered through a pad of celite and washed with MeOH, concentrated,and purified by reverse phase HPLC to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

Procedure 21: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one

In a microwave vial were placed6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(96 mg, 0.18 mmol), 3-fluoropyridin-4-amine (59 mg, 0.53 mmol),Pd₂(dba)₃ (16 mg, 0.02 mmol), Xantphos (20 mg, 0.04 mmol), and cesiumcarbonate (172 mg, 0.53 mmol) in Dioxane (3 mL). The mixture wassonicated, purged with nitrogen gas, and heated to 140° C. for 30minutes. Then the mixture was filtered through a pad of celite andwashed with MeOH, concentrated, and purified by reverse phase HPLC togive1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one.

Procedure 22: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

In a round bottomed flask were placed tert-butyl1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(200 mg, 0.35 mmol),6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (195 mg, 0.71mmol), Pd(PPh₃)₄(20 mg, 0.02 mmol), and cesium carbonate (68 mg, 0.35mmol) in DME (3 mL) and water (1 mL). The reaction mixture was purgedwith nitrogen gas, and heated to 70° C. for 2 h. Then the reactionmixture was filtered through a pad of celite and washed with MeOH,concentrated, and purified by normal phase chromatography eluting with5%-20% MeOH/DCM to give tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of tert-butyl1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

In a microwave vial were placed tert-butyl6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate(64 mg, 0.10 mmol), 3-fluoropyridin-4-amine (34 mg, 0.30 mmol),Pd₂(dba)₃ (9.2 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol), and cesiumcarbonate (99 mg, 0.30 mmol) in Dioxane (3 mL). The reaction mixture wassonicated, purged with nitrogen gas, and heated at 140° C. for 30minutes. Then the reaction mixture was filtered through a pad of celiteand washed with MeOH, concentrated, and purified by reverse phase HPLCto give tert-butyl1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

C. Preparation of1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-onehydrochloride

To a solution of tert-butyl1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate(70 mg, 0.10 mmol) in dichloromethane (2 mL) was added 4N HCl in dioxane(0.5 mL). After stirring at room temperature overnight, the reactionmixture was concentrated under reduced pressure to afford1-((1s,3s)-3-(3,3-dimethylazetidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one.

Procedure 23: Preparation of the Compounds of Formula (18) According toReaction Scheme IV

A. Preparation of tert-butyl6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

In a microwave vial were placed6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine (0.5 g, 1.96 mmol)and tert-butyl1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(1.2 g, 2.06 mmol) in DME (10 mL) and 2M Cs2CO₃ (4.9 mL, 9.8 mmol).After the mixture was purged with nitrogen for 5 minutes, it was heatedat 120° C. for 1 h in the microwave. Then the mixture was cooled to roomtemperature, diluted with water, and extracted with EtOAc. The combinedorganic layers were washed with water and brine, dried (Na₂SO₄), andconcentrated, purified by silica chromatography (10% NH40H inMeOH/EtOAc/hexanes) to give tert-butyl6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

B. Preparation of tert-butyl6-(4-((2,6-difluoropyridin-3-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate

In a microwave vial were placed tert-butyl6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate(0.45 g, 0.72 mmol), 3-bromo-2,6-difluoropyridine (0.28 g, 1.44 mmol),Pd₂(dba)₃ (0.065 g, 0.072 mmol), XantPhos (0.074 g, 0.14 mmol), andCs₂CO₃ (1.17 g, 3.6 mmol) in Dioxane (10 mL). After purging withnitrogen for 5 minutes, the mixture was heated at 120° C. for 30 minutesin the microwave. Then it was diluted with EtOAc, filtered over a bed ofcelite, concentrated, and purified by silica chromatography (10% NH40Hin MeOH/EtOAc/hexanes) to give tert-butyl6-(4-((2,6-difluoropyridin-3-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.

C. Preparation of6-(4-((2,6-difluoropyridin-3-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of tert-butyl6-(4-((2,6-difluoropyridin-3-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate.(0.24 g, 0.33 mmol) in DCM (3.3 mL) was drop-wise added 4M HCl/dioxane(1.6 mL, 6.5 mmol). The mixture was stirred at room temperature for 1 h.The solvent was then evaporated in vacuo and the residue triturated withhexanes. Then, the mixture was concentrated to give6-(4-((2,6-difluoropyridin-3-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one,which was used as is in the next step without further purification.

Procedure 24: Preparation of the Compounds of Formula (I-B) According toReaction Scheme IV

A. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(3-hydroxy-2,2-dimethylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 106)

To a solution of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(0.18 g, 0.26 mmol) in DMF (4 mL) was added3-hydroxy-2,2-dimethylpropanoic acid (0.062 g, 0.53 mmol), DIEA (0.46mL, 2.6 mmol), and HATU (0.2 g, 0.53 mmol). The resulting mixture wasstirred at room temperature for 2 h. It was then quenched with water andextracted twice with EtOAc. The combined organic layers were washed withbrine, dried (Na₂SO₄), concentrated, and purified by reverse phasechromatography (0.01%0 TFA in ACN/0.01% TFA in Water) to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(3-hydroxy-2,2-dimethylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 19, 20, and 21 were used        instead of        6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 19, 20, and 21        were used to prepare the below compounds); and/or    -   carboxylic acids, that are commercially available or can be made        by methods known in the art, such as        1-methoxycyclobutane-1-carboxylic acid, oxetane-2-carboxylic        acid, (1R,2S)-2-hydroxycyclopentane-1-carboxylic acid,        3-methyloxetane-3-carboxylic acid,        (S)-tetrahydrofuran-2-carboxylic acid, (S)-2-hydroxypropanoic        acid, (R)-2-hydroxypropanoic acid, (R)-2-hydroxybutanoic acid,        (S)-2-hydroxybutanoic acid, (R)-2-hydroxy-3-methylbutanoic acid,        (S)-2-hydroxy-3-methylbutanoic acid, 2-hydroxyacetic acid, and        oxetane-3-carboxylic acid, and        1-(hydroxymethyl)cyclopropane-1-carboxylic acid were used        instead of 3-hydroxy-2,2-dimethylpropanoic acid:

Structure Example #

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B. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((1s,3S)-3-methoxycyclobutane-1-carbonyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 136)

To a solution of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(400 mg, 0.66 mmol) in DMF (3 mL) were added(1s,3s)-3-methoxycyclobutane-1-carboxylic acid (171, 1.3 mmol), DIEA(1.1 mL, 6.6 mmol) and a 50% solution of propylphosphonic anhydride(T3P) in EtOAc, (0.78 mL, 1.3 mmol). The resulting mixture was stirredat room temperature for 2 h, and then it was quenched with water andextracted twice with dichloromethane. The combined organic layers werewashed with brine, dried (Na₂SO₄), concentrated, and purified by silicachromatography eluting with 5%-10% MeOH/DCM followed by reverse phaseHPLC to yield6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((1s,3S)-3-methoxycyclobutane-1-carbonyl)-1-((1s,3S)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 19, 20, and 21 were used        instead of        6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 19, 20, and 21        were used to prepare the below compounds); and    -   carboxylic acids, that are commercially available or can be made        by methods known in the art, such as        3-isopropyloxetane-3-carboxylic, 3-ethyloxetane-3-carboxylic        acid, 3-fluoro-2,2-dimethylpropanoic acid,        3-methoxy-2,2-dimethylpropanoic acid, 2-cyano-2-methylpropanoic        acid, 1-cyanocyclopropane-1-carboxylic acid,        cyclopropanecarboxylic acid, oxetane-3-carboxylic acid,        2-methoxy-2-methylpropanoic acid,        1-methoxycyclopropane-1-carboxylic acid,        3-methyloxetane-3-carboxylic acid, isobutyric acid,        1-fluorocyclobutane-1-carboxylic acid,        1-fluorocyclopropane-1-carboxylic acid,        3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid,        (S)-2-methoxypropanoic acid, (R)-2-methoxypropanoic acid,        oxazole-4-carboxylic acid, isoxazole-3-carboxylic acid,        (1r,3r)-3-methoxycyclobutane-1-carboxylic acid,        oxazole-5-carboxylic acid, oxazole-2-carboxylic acid,        1,2,4-oxadiazole-3-carboxylic acid,        1-methyl-1H-1,2,3-triazole-5-carboxylic acid,        thiazole-2-carboxylic acid, acetic acid and        3-hydroxy-2,2-dimethylpropanoic acid were used instead of        (1s,3s)-3-methoxycyclobutane-1-carboxylic acid:

Ex- ample Structure #

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C. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1′-propionylspiro[indoline-3,4′-piperidin]-2-one(Example 167)

To a mixture of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(0.13 g, 0.19 mmol) and triethylamine (0.26 mL, 1.86 mmol) in DCM (2 mL)was added propionyl chloride (0.026 g, 0.23 mmol). The mixture wasstirred at room temperature overnight, and then was loaded directly on asilica cartridge and purified by silica chromatography (10% NH₄OH inMeOH/EtOAc/hexanes) followed by reverse phase chromatography (0.01% TFAin ACN/0.01% TFA in H₂O) to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1′-propionylspiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedures 19 and 20 were used        instead of        6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedures 19 and 20 were        used to prepare the below compounds); and/or    -   acid anhydride or acid chlorides, that are commercially        available or can be made by methods known in the art, such as        pivaloyl chloride and isobutyryl chloride, were used instead of        propionyl chloride:

Structure Example #

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D. Preparation of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(Example 174)

To a solution of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(100 mg, 0.164 mmol) and oxetanone (36 mg, 0.493 mmol) in MeOH (1 mL)were added zinc chloride (34 mg, 2.46 mmol) and sodium cyanoborohydride(19 mg, 4.93 mmol). The mixture was heated at 40° C. for 6 h., thenconcentrated and purified by normal flash chromatography (100% DCM to50% MeOH in DCM) followed by reverse phase chromatography to give6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure exceptthe compounds listed under Procedures 19, 20, and 22 were used insteadof6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4′-piperidin]-2-one(a skilled artisan will readily recognize without undue experimentationwhich compounds of Procedures 19, 20, and 22 were used to prepare thebelow compounds):

Structure Example #

175

176

Procedure 25: Preparation of the Compounds of Formula (19) According toReaction Scheme V

A. Preparation of1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4′-piperidin]-2-one

To a solution oftert-butyl-2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate(2 g, 4.03 mmol) in Dioxane (10 mL) was added 4M HCl in dioxane (10 ml,40 mmol). The mixture was stirred at room temperature for 1 h., and thenconcentrated under reduced pressure to afford1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4′-piperidin]-2-one.

B. Preparation of1′-acetyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one

To a suspension of1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-onehydrochloride (1.74 g, 4.03 mmol) in DCM (50 mL) was added aceticanhydride (3.8 mL, 40 mmol) followed by N, N-Diisopropylethylaamine(14.4 mL, 80 mmol). After stirring at room temperature for 1 h, thereaction was quenched with sat. NaHCO₃ and extracted with DCM. Thecombined organic layers were washed with water and brine, andconcentrated under reduced pressure to afford1′-acetyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidin]-2-one.

C. Preparation of1′-acetyl-6-[4-[(3-fluoro-4-pyridyl)amino]-3-isopropyl-imidazo[4,5-c]pyridin-6-yl]-1-(3-oxocyclobutyl)spiro[indoline-3,4′-piperidine]-2-one

In a sealed tube were placed1′-acetyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-2-one(1.5 g, 3.4 mmol),6-bromo-N-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine(1.44 g, 4.1 mmol), Pd(PPh₃)₄(0.40 g, 0.34 mmol), and 2 M sodiumcarbonate solution (8.6 mL) in DME (30 mL). The mixture was heated at90° C. for 1 h., then cooled to room temperature, diluted with EtOAc (50mL) and water (50 mL), and extracted with EtOAc (50 mL). The combinedorganic layers were concentrated and purified by column chromatography(0-20% DCM eOH) to give1′-acetyl-6-[4-[(3-fluoro-4-pyridyl)amino]-3-isopropyl-imidazo[4,5-c]pyridin-6-yl]-1-(3-oxocyclobutyl)spiro[indoline-3,4′-piperidine]-2-one.

The following compounds were prepared using a similar procedure except3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-onewas used instead of1′-acetyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4′-piperidine]-2-one:

6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-oneProcedure 26: Preparation of the Compounds of Formula I According toReaction Scheme V

A. Preparation of1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1′-acetyl-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one(Example 177)

To a solution of1′-acetyl-6-[4-[(3-fluoro-4-pyridyl)amino]-3-isopropyl-imidazo[4,5-c]pyridin-6-yl]-1-(3-oxocyclobutyl)spiro[indoline-3,4′-piperidine]-2-one(0.12 g, 0.21 mmol) in DCM (1.5 mL) were added 5-azaspiro[2.5]octane(0.12 g, 0.83 mmol), AcOH (0.074 mL, 1.2 mmol), and sodiumtriacetoxyborohydride (131 mg, 0.62 mmol). After stirring at roomtemperature for 2 h, the mixture was diluted with sat. NaHCO₃ (5 mL) andDCM (5 mL). The organic layer was separated, washed with water,concentrated, and purified by normal phase chromatography (0-50%MeOH/DCM) and reverse phase chromatography to give1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1′-acetyl-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)spiro[indoline-3,4′-piperidin]-2-one.

The following compounds were prepared using a similar procedure with thefollowing modification(s):

-   -   the compounds listed under Procedure 25 were used instead of        1′-acetyl-6-[4-[(3-fluoro-4-pyridyl)amino]-3-isopropyl-imidazo[4,5-c]pyridin-6-yl]-1-(3-oxocyclobutyl)spiro[indoline-3,4′-piperidine]-2-one        (a skilled artisan will readily recognize without undue        experimentation which compounds of Procedure 25 were used to        prepare the below compounds); and/or    -   amines, that are commercially available or can be made by        methods known in the art, such as 5-azaspiro[2.4]heptane,        2-methoxy-N,2-dimethylpropan-1-amine, 3-azabicyclo[3.1.0]hexane,        3-azabicyclo[3.2.1]octane, 6-azaspiro[3.5]nonane,        3-azabicyclo[4.1.0]heptane, (S)-2-methylpiperidine, azepane,        (1R,5S)-8-azabicyclo[3.2.1]octane,        1-methyl-3-azabicyclo[3.1.0]hexane, pyrrolidine,        3,3-dimethylpyrrolidine, 3-oxa-6-azabicyclo[3.1.1]heptane,        (R)-3-methylpiperidine, 2-azabicyclo[2.2.2]octane, and        (R)-3-methylpyrrolidine were used instead of        5-azaspiro[2.5]octane:

Structure Example #

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

Procedure 27: Preparation of the Compounds of Formula I According toReaction Scheme II

A. Preparation of methyl2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-5-methylisonicotinate

To a solution of6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one(500 mg, 1.01 mmol) in dioxane (10 ml) were added methyl2-amino-5-methylisonicotinate (338 mg, 2.03 mmol), Pd₂(dba)₃ (93 mg,0.102 mmol), Xanthphos (105 mg, 0.203 mmol), and Cs₂CO₃ (1.6 g, 0.9mmol). The resulting mixture was degassed by bubbling argon gas throughfor 3 min, and then the reaction vessel was sealed. After heating in themicrowave reactor at 130° C. for 30 minutes, the reaction mixture wasfiltered, concentrated, and purified by flash chromatography(Hexanes/EtOAc) to afford methyl2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-5-methylisonicotinate.

B. Preparation of2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-5-methylisonicotinicacid

To a stirring solution of methyl2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-5-methylisonicotinate(560 mg, 0.901 mmol) in THE (20 ml) and MeOH (10 ml) was added LiOH—H₂O(43 mg, 1.8 mmol). The resulting mixture was warmed to 40° C. thenstirred for 15 h. After cooling to room temperature, the reactionmixture was concentrated to give2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-5-methylisonicotinicacid, which was used in the next step without further purification.

C. Preparation of2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,5-dimethylisonicotinamideExample 194

To a stirring solution of2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-5-methylisonicotinicacid (400 mg, 0.461 mmol) in DMF (5 ml) were added methanaminehydrochloride (62 mg, 0.92 mmol), HATU (351 mg, 0.92 mmol), and DIEA(0.48 ml, 2.76 mmol). The resulting mixture was stirred until thestarting material was sufficiently consumed. The reaction solution wasquenched with water and the aqueous layer was extracted with EtOAc. Thecombined organic layer was washed with brine, dried over Na₂SO₄,concentrated, and purified by reverse flash chromatography to give2-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,5-dimethylisonicotinamide.

The following compounds were prepared using a similar procedure except1-(fluoromethyl)cyclopropan-1-amine was used instead of methanaminehydrochloride:

Structure Example #

195

Procedure 28: Preparation of the Compounds of Formula (8) Shown inReaction Scheme I

A. Preparation of 4-amino-5-fluoro-N-methylpicolinamide

To a mixture of 4-amino-5-fluoropicolinic acid, DIEA (1.0 ml, 5.8 mmol),and HATU (439.6 mg, 1.2 mmol) was added methanamine in 2 M THE (1.4 mL,2.9 mmol) in ACN (4 mL). After stirring at 60° C. overnight, the mixturewas concentrated and diluted with DCM and sat. NaHCO₃. The aqueous layerwas discarded and the organic layer was concentrated to give4-amino-5-fluoro-N-methylpicolinamide, which was used in the next stepwithout further purification.

The following compounds were prepared using a similar procedure exceptisopropylamine was used instead of methanamine:

Procedure 29: Preparation of the Compounds of Formula (20) Shown inReaction Scheme III

A. Preparation of 6-bromo-5-fluoro-N-methylpicolinamide

To a mixture of 6-bromo-5-fluoropicolinic acid, DIEA (1.0 ml, 5.8 mmol),and HATU (416.6 mg, 1.2 mmol) was added methanamine in 2 M THE (1.4 mL,2.9 mmol) in ACN (5 mL). After stirring at 60° C. overnight, the mixturewas concentrated and diluted with DCM and sat. NaHCO₃. The aqueous layerwas discarded and the organic layer was concentrated to give6-bromo-5-fluoro-N-methylpicolinamide, which was used in the next stepwithout further purification.

Chiral Resolution 1. Separation of the isomers of6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3-hydroxy-3-methyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one(Example 55) was separated on CHIRALPAK IA SFC Sum 21×250 mm column in35% MeOH (modified with 10 mM NH₃)/CO₂ at 60 mL/min to give the twosingle isomers:

Separation Peak Example Name method # # 6-(4-((3-fluoropyridin-4-CHIRALPAK IA 1^(st) 55A yl)amino)-3-isopropyl-3H- SFC 5 um elutingimidazo[4,5-c]pyridin-6- 21 × 250 mm column peak yl)-3-hydroxy-3-methyl-in 35% MeOH 2^(nd) 55B 1-((1s,3s)-3-(piperidin-1- (modified with 10eluting yl)cyclobutyl)indolin-2- mM NH₃)/CO₂ at peak one 60 mL/min

2. Separation of the Isomers of1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetane-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(oxetane-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one(Example 78) was separated on SFC using CHIRALPAK IB-column (5 um 21mm×250 ml) to give the two single isomers:

Separation Peak Example Name method # # 1-((1s,3s)-3-(3,3- SFC CHIRALPAK1^(st) 78A dimethylpyrrolidin-1- IB 5 um elutingyl)cyclobutyl)-6-(4-((3- 21 × 250 mm peak fluoropyridin-4-yl)amino)-3-column in 35% 2^(nd) 78B isopropyl-3H-imidazo[4,5- EtOH (modifiedeluting c]pyridin-6-yl)-1′-(oxetane-2- with 10 mM peakcarbonyl)spiro[indoline-3,4′- NH3)/CO2 at piperidin]-2-one 60 mL/min

3. Separation of the Isomers of1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(2-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-(2-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one(Example 15) was separated on CHIRALPAK IB 4.6×100 mm 5mic column in 35%MeOH—NH₃ at 3.0 mL/min to give the two single isomers:

Separation Peak Example Name method # # 1-((1s,3s)-3-(3,3- CHIRALPAK IB1^(st) 15A dimethylpyrrolidin-1- 4.6 × 100 mm 5 mic elutingyl)cyclobutyl)-6-(4-((3- column in 35% peak fluoropyridin-4-yl)amino)-3-MeOH—NH₃ at 2^(nd) 15B isopropyl-3H-imidazo[4,5- 3.0 mL/min elutingc]pyridin-6-yl)-1′-(2- peak methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′- piperidin]-2-one

4. Separation of the Mixture of1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2R,3S)-3-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-oneand1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2S,3R)-3-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

The mixture of1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2R,3S)-3-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-oneand1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2S,3R)-3-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one(Examples 19A and 19B) was separated on CHIRALPAK IB 4.6×100 mm 5miccolumn in 35% MeOH—NH₃ at 3.0 mL/min to give the two single isomers.

Separation Peak Example Name method # #1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6- CHIRALPAK1^(st) 19A (4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H- IB elutingimidazo[4,5-c]pyridin-6-yl)-1′-((2R,3S)-3- 4.6 × 100 mm peakmethyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′- 5 mic columnpiperidin]-2-one in 35% and MeOH—NH₃1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6- at 3.0 mL/min2^(nd) 19B (4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H- elutingimidazo[4,5-c]pyridin-6-yl)-1′-((2S,3R)-3- peakmethyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-onecarbonyl)spiro[indoline-3,4′-piperidin]- 2-one

5. Separation of the Mixture of1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2R,5R)-5-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-oneand1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2S,5S)-5-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

The mixture of1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2R,5R)-5-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-oneand1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1′-((2S,5S)-5-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one(Examples 20A and 20B) was separated on CHIRALPAK IB 4.6×100 mm 5miccolumn in 50% IPA-NH3 at 3.0 mL/min to give the two single isomers.

Separation Peak Example Name method # #1-((1s,3S)-3-(3,3-dimethylpyrrolidin-1- CHIRALPAK 1^(st) 20Ayl)cyclobutyl)-6-(4-((3-fluoropyridin-4- IB elutingyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin- 4.6 × 100 mm peak6-yl)-1′-((2R,5R)-5-methyltetrahydrofuran-2- 5 mic columncarbonyl)spiro[indoline-3,4′-piperidin]-2-one in 50% and IPA-NH₃1-((1s,3R)-3-(3,3-dimethylpyrrolidin-1- at 3.0 mL/min 2^(nd) 20Byl)cyclobutyl)-6-(443-fluoropyridin-4- elutingyl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin- peak6-yl)-1′-((2S,5S)-5-methyltetrahydrofuran-2-carbonyl)spiro[indoline-3,4′-piperidin]-2-one

Analytical Data for Examples 1 to 195 are set forth in Table 1.

HPK1 IC₅₀ Assay

The enzymatic activity of human HPK1 (MAP4K1) was monitored in abiochemical assay in the presence or absence of compounds and using asynthetic peptide substrate. An increase in phosphorylation of thepeptide by HPK1 was indicative of its kinase activity.

Recombinant HPK1 kinase domain produced via baculovirus infection ofinsect cells was obtained from Proteros (Proteros Biostructures#PR-0322) and was pre-activated in the presence of 2 mM ATP(Sigma-Aldrich, cat #GE27-2056-01) and 2 mM magnesium chloride for 16hours at 4° C. The protein reaction mixture was then loaded to adesalting column (Thermo Fisher Scientific, Cat #89889) to remove excessATP. HPK1 was eluted with buffer containing 20 mM Tris(2-Amino-2-(hydroxymethyl)propane-1,3-diol) pH 8.0, 150 mM NaCl, 2 mMdithiothreitol and 5% glycerol, and was frozen at −80° C. for later use.HPK1 dual phosphorylation was confirmed by mass spectrometry.

Ten nanoliters of test compounds dissolved in DMSO at variousconcentrations were dispensed into a 384-well ProxiPlate (PerkinElmer#6008289). Five microliters of a solution of recombinant HPK1 diluted inHPK1 kinase assay buffer (50 mM BES[N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid], pH 7.0; 10 mMmagnesium chloride; 0.01% Triton X-100; 1 mM dithiothreitol; 0.01%bovine serum albumin; 0.1 mM sodium orthovanadate) was added to thecompound-containing plate and was incubated for 15 minutes at 25° C.Five microliters of a mixture of ATP (Sigma-Aldrich #A6559) and peptidesubstrate STK S1 (Cisbio #61ST1BLC) diluted in HPK1 kinase assay bufferwas then added to start the reaction. Final concentrations were 0.15 nMfor HPK1, 10 μM for ATP, and 1 μM for the STK S1 peptide substrate. Thereaction mixture was incubated at 25° C. for 3 hours and was stoppedwith the addition of 10 μl of an EDTA (Ethylenediaminetetraaceticacid)-containing detection buffer (Cisbio 9 62SDBRDF) supplemented withEuropium cryptate-labeled anti-phospho-serine/threonine antibodies(Cisbio 9 62ST1PEJ) and XL665-labeled streptavidin (Cisbio 9 610SAXLG).The mixture was incubated for 16 hours at room temperature and peptidephosphorylation was measured by time-resolved fluorescence energytransfer (665 nm/620 nm) on an Envision plate reader (PerkinElmer).

Data in Table 1 were normalized based on positive (staurosporine) andnegative (DMSO) controls. Least squares curve fittings were performedusing a four-parameter variable slope nonlinear regression model. IC₅₀is defined as the concentration of compound required to inhibit 5000 ofmaximum phosphorylation. IC₅₀ values from multiple experiments wereaveraged by geometric mean and the standard deviation was calculated.

TABLE 1 Example ES/MS HPK1 # m/z ¹H-NMR IC₅₀ (nM)  1 735.5 1H NMR (400MHz, DMSO-d6) delta 10.52 (d, J = 56.3 Hz, 0.6 2H), 8.91 (d, J = 5.3 Hz,1H), 8.77 (s, 1H), 8.47-8.14 (m, 2H), 7.84-7.43 (m, 4H), 5.13 (p, J =6.6 Hz, 1H), 4.48-4.05 (m, 1H), 4.02-3.48 (m, 6H), 3.34 (dddd, J = 34.6,25.8, 15.6, 10.9 Hz, 4H), 3.09-2.66 (m, 6H), 2.56-2.36 (m, 4H),2.03-1.32 (m, 15H), 1.26-1.00 (m, 6H).  2 681.4 1H NMR (400 MHz,DMSO-d6) delta 10.68(s, 1H), 9.73 (s, 0.5 1H), 8.92 (d, J = 5.4 Hz, 1H),8.77 (s, 1H), 8.39 (d, J = 6.6 Hz, 1H), 8.34 (s, 1H), 7.79 (dd, J = 7.8,1.5 Hz, 1H), 7.75-7.56 (m, 3H), 7.53 (d, J = 7.8 Hz, 1H), 5.12 (p, J =6.6 Hz, 1H), 4.48 (q, J = 6.5 Hz, 1H), 4.38-4.18 (m, 1H), 4.07-3.76 (m,4H), 3.77- 3.63 (m, 0H), 3.56-3.43 (m, 1H), 3.38 (d, J = 11.7 Hz, 2H),2.94 (dd, J = 17.3, 9.1 Hz, 2H), 2.89-2.66 (m, 3H), 1.70 (ddt, J = 52.1,42.1, 13.5 Hz, 10H), 1.51 (d, J = 6.6 Hz, 6H), 1.41 (dd, J = 23.8, 11.2Hz, 1H), 1.22(t, J = 6.9 Hz, 4H).  3 695.4 1H NMR (400 MHz, DMSO-d6)delta 10.34 (s, 1H), 9.40 (s, 0.6 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.74(s, 1H), 8.38-8.28 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H),7.64-7.56 (m, 2H), 5.60- 3.70 (m, 2H), 5.48 (s, 1H), 5.13 (p, J = 6.6Hz, 1H), 4.36-4.05 (m, 3H), 3.48 (q, J = 7.9 Hz, 1H), 3.40 (d, J = 11.7Hz, 2H), 3.01- 2.90 (m, 2H), 2.89-2.75 (m, 4H), 1.91-1.56 (m, 9H), 1.52(d, J = 6.6 Hz, 6H), 1.47-1.34 (m, 7H).  4 709.4 1H NMR (400 MHz,DMSO-d6) delta 10.41 (s, 1H), 10.24 (S, 0.4 1H), 8.85 (d, J = 5.1 Hz,1H), 8.75 (s, 1H), 8.35 (d, J = 6.4 Hz, 1H), 8.33 (s, 1H), 7.80 (d, J =7.7 Hz, 1H), 7.69-7.65 (m, 1H), 7.61 (dd, J = 16.1, 7.5 Hz, 2H),5.62-3.74 (m, 5H), 5.12 (p, J = 6.7 Hz, 1H), 3.75-3.54 (m, 2H),3.38-3.30 (m, 1H), 3.29-3.18 (m, 1H), 3.04-2.91 (m, 2H), 2.87-2.75 (m,3H), 1.97-1.87 (m, 1H), 1.84-1.62 (m, 5H), 1.52 (d, J = 6.6 Hz, 6H),1.37 (s, 6H), 1.18 (s, 3H), 1.11 (s, 3H).  5 719.4 1H NMR (400 MHz,DMSO-d6) delta 10.48 (s, 2H), 8.87 (d, J = 0.5 5.2 Hz, 1H), 8.76 (s,1H), 8.41-8.28 (m, 2H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.71-7.56 (m,3H), 5.13 (p, J = 6.6 Hz, 1H), 4.86 (dd, J = 17.8, 5.9 Hz, 2H), 4.39 (p,J = 8.5 Hz, 1H), 4.31 (t, J = 6.5 Hz, 2H), 4.00-3.86 (m, 1H), 3.83-3.59(m, 3H), 3.57-3.47 (m, 1H), 3.36-3.22 (m, 2H), 3.22-3.09 (m, 2H),3.08-2.88 (m, 2H), 2.88-2.78 (m, 2H), 2.13-2.03 (m, 1H), 1.96-1.87 (m,1H), 1.87-1.70 (m, 4H), 1.60 (s, 3H), 1.52 (d, J = 6.6 Hz, 6H),0.81-0.68 (m, 3H), 0.65 (s, 1H).  6 753.4 1H NMR (400 MHz, DMSO-d6)delta 9.66-9.53 (m, 1H), 8.71 0.5 (s, 1H), 8.51 (s, 1H), 8.12 (d, J =7.8 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J = 7.8, 1.5 Hz, 1H), 7.64 (s, 1H),7.58-7.44 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.59 (t, J = 53.7 Hz, 2H),5.32 (p, J = 6.5 Hz, 1H), 4.28 (p, J = 8.4 Hz, 1H), 4.11-3.98 (m, 1H),3.80 (s, 2H), 3.64 (s, 2H), 3.54-3.30 (m, 5H), 2.98-2.88 (m, 2H), 2.88-2.73 (m, 4H), 2.31 (s, 3H), 2.26-1.89 (m, 4H), 1.84 (d, J = 14.1 Hz,2H), 1.76-1.59 (m, 3H), 1.57 (d, J = 6.5 Hz, 6H), 1.48- 1.35 (m, 1H),1.10 (d, J = 6.6 Hz, 6H).  7 719.4 1H NMR (400 MHz, DMSO-d6) delta10.50-9.85 (m, 2H), 0.2 8.91-8.69 (m, 2H), 8.90-8.70 (m, 2H), 8.40-8.26(m, 1H), 7.82-7.77 (m, 1H), 7.68-7.57 (m, 3H), 5.19-5.08 (m, 1H),4.92-4.81 (m, 2H), 4.37-4.27 (m, 4H), 3.97-3.88 (m, 1H), 3.82-3.67 (m,5H), 3.57-3.42 (m, 1H), 3.34-3.12 (m, 3H), 3.10-2.92 (m, 2H), 2.88-2.78(m, 2H), 2.31-2.10 (m, 2H), 1.88-1.70 (d, J = 21.0 Hz, 5H), 1.60 (s,3H), 1.53 (d, J = 6.6 Hz, 7H).  8 721.4 1H NMR (400 MHz, DMSO-d6) delta10.54-10.08 (m, 2H), 0.2 8.84 (d, J = 17.3 Hz, 1H), 8.77-8.72 (m, 1H),8.40-8.25 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.70-7.57 (m, 3H),5.19-5.06 (m, 1H), 4.92-4.81 (m, 2H), 4.42-4.28 (m, 3H), 3.97-3.88 (m,1H), 3.82-3.72 (m, 1H), 3.72-3.56 (m, 2H), 3.56-3.47 (m, 1H), 3.30-3.13(m, 3H), 3.03-2.87 (m, 2H), 2.85-2.71 (m, 3H), 2.55-2.34 (m, 2H),1.86-1.70 (m, 4H), 1.60 (s, 3H), 1.52 (d, J = 6.6 Hz, 6H), 1.13-0.82 (m,6H).  9 721.4 1H NMR (400 MHz, DMSO-d6) delta 10.48 (s, 1H), 10.38- 0.210.15 (m, 1H), 8.87 (s, 1H), 8.76 (s, 1H), 8.36 (d, J = 6.0 Hz, 1H),8.33 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.65- 7.54 (m,2H), 5.12 (p, J = 6.6 Hz, 1H), 4.73 (t, J = 6.7 Hz, 1H), 4.43-4.30 (m,1H), 4.00-3.71 (m, 6H), 3.71-3.55 (m, 2H), 3.32-3.15 (m, 2H), 3.04-2.88(m, 2H), 2.85-2.71 (m, 3H), 2.53-2.44 (m, 1H), 2.43-2.34 (m, 1H),2.21-1.96 (m, 2H), 1.96-1.76 (m, 4H), 1.75-1.66 (m, 2H), 1.52 (d, J =6.6 Hz, 6H), 0.95 (dd, J = 18.5, 6.1 Hz, 6H). 10 723.4 1H NMR (400 MHz,DMSO-d6) delta 9.06 (s, 1H), 8.63 (s, 1H), 0.05 8.43 (d, J = 3.3 Hz,1H), 8.19 (d, J = 5.4 Hz, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.74 (d, J =7.8 Hz, 1H), 7.59-7.53 (m, 2H), 5.19 (p, J = 6.6 Hz, 1H), 4.57 (t, J =5.9 Hz, 1H), 4.47 (bs, 1H), 3.98- 3.83 (m, 4H), 3.46 (d, J = 6.0 Hz,2H), 3.33-3.28 (m, 2H), 2.96 (s, 1H), 2.84-2.60 (m, 3H), 2.50-2.39 (m,2H), 2.36-2.25 (m, 1H), 1.95-1.80 (m, 1H), 1.78-1.66 (m, 4H), 1.53 (d, J= 6.6 Hz, 6H), 1.21 (s, 6H), 0.88 (d, J = 5.9 Hz, 6H). 11 707.4 1H NMR(400 MHz, DMSO-d6) delta 10.33-10.01 (m, 1H), 0.2 9.46-9.30 (m, 1H),8.86-8.67 (m, 2H), 8.38-8.23 (m, 2H), 7.78 (d, J = 7.9 Hz, 1H),7.70-7.54 (m, 3H), 5.14 (p, J = 6.1 Hz, 1H), 4.44 (q, J = 8.4, 8.0, 5.7Hz, 1H), 4.37-4.20 (m, 2H), 4.01-3.65 (m, 4H), 3.53-3.32 (m, 3H),3.17-3.04 (m, 1H), 3.03-2.74 (m, 7H), 1.93-1.34 (m, 19H). 12 721.4 1HNMR (400 MHz, DMSO-d6) delta 10.25-10.04 (m, 2H), 0.1 8.82-8.76 (m, 1H),8.73 (s, 1H), 8.33 (d, J = 6.2 Hz, 1H), 8.29 (s, 1H), 7.78 (d, J = 7.9Hz, 1H), 7.69-7.52 (m, 3H), 5.20-5.07 (m, 1H), 4.44 (q, J = 7.8 Hz, 1H),4.40-4.24 (m, 2H), 4.00- 3.54 (m, 6H), 3.39-3.18 (m, 2H), 3.16-3.04 (m,1H), 3.03- 2.89 (m, 2H), 2.87-2.74 (m, 3H), 1.97-1.66 (m, 7H), 1.63 (d,J = 10.2 Hz, 3H), 1.53 (d, J = 6.6 Hz, 6H), 1.15 (d, J = 24.5 Hz, 6H).13 721.4 1H NMR (400 MHz, DMSO-d6) delta 10.58 (s, 1H), 10.42 (s, 0.21H), 8.90 (dd, J = 5.6, 2.6 Hz, 1H), 8.77 (d, J = 1.1 Hz, 1H), 8.39 (dd,J = 6.6, 1.8 Hz, 1H), 8.34 (s, 1H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H),7.69-7.54 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.74 (dd, J = 7.7, 5.7 Hz,1H), 4.36 (p, J = 8.4 Hz, 1H), 4.01-3.53 (m, 6H), 3.39-3.16 (m, 2H),2.97 (d, J = 12.8 Hz, 2H), 2.82 (s, 3H), 2.22- 1.96 (m, 2H), 1.97-1.59(m, 8H), 1.53 (d, J = 6.6 Hz, 7H), 1.15 (d, J = 24.8 Hz, 6H). 14 721.41H NMR (400 MHz, DMSO-d6) delta 10.64 (s, 1H), 10.49 (s, 0.2 1H), 8.92(dd, J = 5.5, 1.9 Hz, 1H), 8.78 (s, 1H), 8.40 (d, J = 6.6 Hz, 1H), 8.35(s, 1H), 7.80 (dd, J = 7.8, 1.5 Hz, 1H), 7.70-7.54 (m, 3H), 5.13 (p, J =6.7 Hz, 1H), 4.79-4.69 (m, 1H), 4.36 (h, J = 8.5, 7.9 Hz, 1H), 3.99-3.55(m, 6H), 3.39-3.15 (m, 2H), 2.99 (dq, J = 22.4, 9.4 Hz, 2H), 2.82 (d, J= 9.7 Hz, 4H), 2.22-1.96 (m, 2H), 1.96-1.64 (m, 8H), 1.53 (d, J = 6.6Hz, 6H), 1.15 (d, J = 25.2 Hz, 7H). 15 735.4 1H NMR (400 MHz, DMSO-d6)delta 10.48 (s, 2H), 8.88 (q, J = 0.2 4.7 Hz, 1H), 8.76 (t, J = 1.5 Hz,1H), 8.41-8.30 (m, 2H), 7.79 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 (d, J = 7.2Hz, 3H), 5.14 (p, J = 6.7 Hz, 1H), 4.33 (dt, J = 23.0, 11.5 Hz, 2H),3.91 (td, J = 7.9, 5.9 Hz, 2H), 3.85-3.56 (m, 3H), 3.40-3.17 (m, 2H),2.97 (t, J = 9.8 Hz, 2H), 2.81 (s, 3H), 2.75-2.63 (m, 1H), 1.97-1.56 (m,9H), 1.53 (d, J = 6.6 Hz, 7H), 1.44 (s, 4H), 1.15 (d, J = 25.3 Hz, 7H). 15A 735.4 1H NMR (400 MHz, DMSO-d6) delta 10.55 (s, 1H), 10.36 (s, 0.2(1^(st) 1H), 8.90 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.40-8.33 (m, 2H),eluting 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.69-7.54 (m, 3H), 5.13 (p, J =peak) 6.6 Hz, 1H), 4.34 (dt, J = 27.2, 13.5 Hz, 2H), 4.15-3.86 (m, 4H),3.67 (tt, J = 17.0, 10.5 Hz, 2H), 3.39-3.14 (m, 2H), 2.98 (d, J = 10.0Hz, 2H), 2.87-2.64 (m, 4H), 1.98-1.36 (m, 20H), 1.15 (d, J = 25.2 Hz,6H).  15B 735.4 1H NMR (400 MHz, DMSO-d6) delta 10.61 (s, 1H), 10.42 (s,0.2 (2^(nd) 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.42-8.33 (m,2H), eluting 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.72-7.53 (m, 3H), 5.13 (p,J = peak) 6.6 Hz, 1H), 4.34 (dt, J = 26.4, 13.1 Hz, 2H), 4.15-3.52 (m,5H), 3.42-3.13 (m, 2H), 2.98 (d, J = 10.4 Hz, 2H), 2.90-2.62 (m, 4H),1.98-1.36 (m, 21H), 1.15 (d, J = 25.4 Hz, 7H). 16 721.4 1H NMR (400 MHz,DMSO-d6) delta 10.61 (s, 2H), 8.92 (d, J = 0.3 5.2 Hz, 1H), 8.78 (s,1H), 8.41 (d, J = 6.6 Hz, 1H), 8.34 (s, 1H), 7.80 (dd, J = 7.8, 1.4 Hz,1H), 7.74-7.50 (m, 3H), 5.15 (p, J = 6.6 Hz, 1H), 4.43-4.29 (m, 1H),4.03-3.54 (m, 7H), 3.51-3.18 (m, 3H), 2.97 (ddd, J = 20.3, 13.6, 6.1 Hz,2H), 2.82 (q, J = 8.0, 7.6 Hz, 3H), 2.16-2.00 (m, 3H), 1.97-1.67 (m,7H), 1.53 (d, J = 6.6 Hz, 6H), 1.15 (d, J = 25.7 Hz, 6H). 17 721.4 1HNMR (400 MHz, DMSO-d6) delta 10.63 (s, 1H), 10.49 (s, 0.3 1H), 8.92 (d,J = 4.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.40 (dd, J = 6.9, 2.6 Hz,1H), 8.35 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70- 7.58 (m, 3H), 5.13(p, J = 6.7 Hz, 1H), 4.36 (p, J = 8.3 Hz, 1H), 4.00-3.56 (m, 8H),3.49-3.17 (m, 3H), 2.99 (dp, J = 18.6, 9.3 Hz, 2H), 2.89-2.73 (m, 3H),2.07 (dddd, J = 18.9, 12.4, 9.3, 5.3 Hz, 2H), 1.98-1.86 (m, 1H), 1.76(dt, J = 24.8, 6.2 Hz, 6H), 1.53 (d, J = 6.6 Hz, 6H), 1.15 (d, J = 25.1Hz, 6H). 18 735.4 1H NMR (400 MHz, DMSO-d6) delta 10.63 (s, 2H), 8.93(t, J = 0.3 4.8 Hz, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.44-8.32 (m, 2H),7.80 (d, J = 7.8 Hz, 1H), 7.71-7.60 (m, 3H), 5.14 (p, J = 6.7 Hz, 1H),4.36 (p, J = 8.4 Hz, 1H), 4.04 (d, J = 8.7 Hz, 1H), 3.92-3.52 (m, 8H),3.40-3.19 (m, 2H), 2.98 (q, J = 9.9 Hz, 2H), 2.86-2.76 (m, 4H), 2.37(dt, J = 15.2, 8.0 Hz, 1H), 1.84 (dt, J = 52.4, 6.6 Hz, 7H), 1.53 (d, J= 6.6 Hz, 6H), 1.35 (s, 3H), 1.15 (d, J = 25.6 Hz, 6H). 19A and 735.4 1HNMR (400 MHz, DMSO-d6) delta 10.52 (d, J = 66.3 Hz, 0.3 19B 2H), 8.92(td, J = 5.5, 5.1, 2.4 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.40 (t, J =5.4 Hz, 1H), 8.35 (s, 1H), 7.80 (dd, J = 8.5, 3.3 Hz, 1H), 7.66 (t, J =5.3 Hz, 2H), 7.59 (d, J = 7.9 Hz, 1H), 5.13 (ddt, J = 12.3, 8.3, 5.4 Hz,1H), 4.83 (dd, J = 10.2, 7.0 Hz, 1H), 4.36 (p, J = 8.4 Hz, 1H),4.04-3.52 (m, 7H), 3.39-3.16 (m, 2H), 2.99 (tt, J = 18.9, 9.6 Hz, 2H),2.81 (s, 3H), 2.57 (p, J = 7.0 Hz, 1H), 2.12-2.00 (m, 1H), 1.98-1.58 (m,7H), 1.56-1.48 (m, 6H), 1.15 (d, J = 25.1 Hz, 6H), 0.99 (d, J = 7.0 Hz,1H), 0.92 (d, J = 7.0 Hz, 2H)  19A 735.4 1H NMR (400 MHz, DMSO-d6) delta10.58 (s, 1H), 10.40 (s, 0.2 (1^(st) 1H), 8.93-8.87 (m, 1H), 8.77 (s,1H), 8.39 (d, J = 6.7 Hz, 1H), eluting 8.35 (s, 1H), 7.80 (ddd, J = 7.9,3.5, 1.5 Hz, 1H), 7.70-7.55 (m, peak) 3H), 5.13 (td, J = 6.6, 2.8 Hz,1H), 4.83 (dd, J = 10.0, 7.0 Hz, 1H), 4.36 (p, J = 8.4 Hz, 1H),4.06-3.52 (m, 6H), 3.40-3.12 (m, 2H), 2.99 (dd, J = 18.2, 9.4 Hz, 2H),2.81 (s, 3H), 2.62-2.51 (m, 2H), 2.14-1.98 (m, 1H), 1.98-1.58 (m, 6H),1.52 (dd, J = 6.7, 2.1 Hz, 6H), 1.15 (d, J = 25.1 Hz, 7H), 0.99 (d, J =7.0 Hz, 1H), 0.92 (d, J = 7.0 Hz, 2H).  19B 735.4 1H NMR (400 MHz,DMSO-d6) delta 10.42 (d, J = 73.1 Hz, 0.1 (2^(nd) 2H), 8.89 (s, 1H),8.76 (t, J = 1.5 Hz, 1H), 8.41-8.32 (m, 2H), eluting 7.79 (dt, J = 8.0,2.2 Hz, 1H), 7.70-7.56 (m, 2H), 5.20-5.08 peak) (m, 1H), 4.83 (dd, J =9.8, 7.0 Hz, 1H), 4.36 (p, J = 8.4 Hz, 1H), 4.04-3.50 (m, 7H), 3.39-3.13(m, 2H), 3.00 (t, J = 9.3 Hz, 2H), 2.81 (s, 3H), 2.57 (p, J = 7.0 Hz,1H), 2.11-1.99 (m, 1H), 1.99- 1.58 (m, 7H), 1.52 (dd, J = 6.7, 2.0 Hz,6H), 1.15 (d, J = 25.0 Hz, 6H), 0.99 (d, J = 7.0 Hz, 1H), 0.92 (d, J =7.0 Hz, 2H). 20A and 735.4 1H NMR (400 MHz, DMSO-d6) delta 10.64 (s,2H), 10.51 (s, 0.2 20B 2H), 8.92 (p, J = 2.2 Hz, 1H), 8.78 (s, 1H), 8.40(dd, J = 6.7, 2.0 Hz, 1H), 8.35 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H),7.70-7.49 (m, 3H), 5.14 (hept, J = 6.7 Hz, 1H), 4.67 (dt, J = 8.3, 4.4Hz, 1H), 4.35 (p, J = 8.3 Hz, 1H), 4.06-3.57 (m, 5H), 3.37-3.18 (m, 2H),2.99 (h, J = 10.8, 9.8 Hz, 2H), 2.82 (d, J = 9.1 Hz, 3H), 2.27 (dh, J =18.5, 4.9, 4.3 Hz, 1H), 2.04-1.62 (m, 7H), 1.53 (d, J = 6.6 Hz, 7H),1.25-1.07 (m, 9H).  20A 735.4 1H NMR (400 MHz, DMSO-d6) delta 10.64 (s,2H), 10.51 (s, 0.1 (1^(st) 2H), 8.92 (p, J = 2.2 Hz, 1H), 8.78 (s, 1H),8.40 (dd, J = 6.7, 2.0 eluting Hz, 1H), 8.35 (s, 1H), 7.80 (d, J = 7.8Hz, 1H), 7.70-7.49 (m, peak) 3H), 5.14 (hept, J = 6.7 Hz, 1H), 4.67 (dt,J = 8.3, 4.4 Hz, 1H), 4.35 (p, J = 8.3 Hz, 1H), 4.06-3.57 (m, 5H),3.37-3.18 (m, 2H), 2.99 (h, J = 10.8, 9.8 Hz, 2H), 2.82 (d, J = 9.1 Hz,3H), 2.27 (dh, J = 18.5, 4.9, 4.3 Hz, 1H), 2.04-1.62 (m, 7H), 1.53 (d, J= 6.6 Hz, 7H), 1.25-1.07 (m, 9H).  20B 735.4 1H NMR (400 MHz, DMSO-d6)delta 10.64 (s, 2H), 10.51 (s, 0.05 (2^(nd) 2H), 8.92 (p, J = 2.2 Hz,1H), 8.78 (s, 1H), 8.40 (dd, J = 6.7, 2.0 eluting Hz, 1H), 8.35 (s, 1H),7.80 (d, J = 7.8 Hz, 1H), 7.70-7.49 (m, peak) 3H), 5.14 (hept, J = 6.7Hz, 1H), 4.67 (dt, J = 8.3, 4.4 Hz, 1H), 4.35 (p, J = 8.3 Hz, 1H),4.06-3.57 (m, 5H), 3.37-3.18 (m, 2H), 2.99 (h, J = 10.8, 9.8 Hz, 2H),2.82 (d, J = 9.1 Hz, 3H), 2.27 (dh, J = 18.5, 4.9, 4.3 Hz, 1H),2.04-1.62 (m, 7H), 1.53 (d, J = 6.6 Hz, 7H), 1.25-1.07 (m, 9H). 21 7211H NMR (400 MHz, Methanol-d4) delta 8.57 (s, 1H), 8.35 (d, 0.4 J = 3.6Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.82-7.68(m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 5.29-5.14 (m, 1H), 4.36-4.25 (m, 1H),4.05-3.84 (m, 2H), 3.70-3.44 (m, 3H), 3.14 (s, 3H), 3.09-2.93 (m, 7H),2.93-2.82 m, 1H), 2.78-2.54 (m, 5H), 2.37 (s, 2H), 2.20-1.88 (m, 4H),1.63 (d, J = 6.6 Hz, 6H), 1.08 (s, 6H). 22 693 1H NMR (400 MHz,Methanol-d4) delta 8.54 (s, 1H), 8.34 (d, 0.3 J = 3.6 Hz, 1H), 8.13 (d,J = 5.6 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.82-7.68 (m, 3H), 7.45 (dd,J = 24.7, 7.9 Hz, 1H), 5.51 (td, J = 7.7, 5.0 Hz, 1H), 5.27-5.14 (m,1H), 4.74-4.49 (m, 2H), 4.24- 3.49 (m, 6H), 2.99-2.82 (m, 2H), 2.67-2.21(m, 8H), 1.96- 1.34 (m, 16H). 23 735.5 1H NMR (400 MHz, DMSO-d6) delta10.45 (d, J = 31.1 Hz, 0.2 2H), 8.87 (t, J = 4.2 Hz, 1H), 8.76 (d, J =1.1 Hz, 1H), 8.46- 8.18 (m, 2H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H),7.69-7.50 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.61-3.53 (m, 12H),3.48-3.11 (m, 4H), 3.06-2.72 (m, 5H), 2.01-1.41 (m, 15H), 1.15 (d, J =24.4 Hz, 6H). 24 735.5 1H NMR (400 MHz, DMSO-d6) delta 10.28 (d, J =32.3 Hz, 0.09 2H), 8.92-8.62 (m, 2H), 8.43-8.23 (m, 2H), 7.87-7.43 (m,4H), 5.12 (q, J = 6.7 Hz, 1H), 4.47-4.13 (m, 2H), 4.06-3.02 (m, 9H),3.09-2.72 (m, 6H), 1.94-1.35 (m, 19H), 1.15 (d, J = 22.3 Hz, 6H). 25735.5 1H NMR (400 MHz, DMSO-d6) delta 10.52 (d, J = 56.3 Hz, 0.2 2H),8.91 (d, J = 5.3 Hz, 1H), 8.77 (s, 1H), 8.47-8.14 (m, 2H), 7.84-7.43 (m,4H), 5.13 (p, J = 6.6 Hz, 1H), 4.48-4.05 (m, 1H), 4.02-3.48 (m, 6H),3.34 (dddd, J = 34.6, 25.8, 15.6, 10.9 Hz, 4H), 3.09-2.66 (m, 6H),2.56-2.36 (m, 4H), 2.03-1.32 (m, 15H), 1.26-1.00 (m, 6H). 26 735.5 1HNMR (400 MHz, DMSO-d6) delta 10.52 (d, J = 56.3 Hz, 0.2 2H), 8.91 (d, J= 5.3 Hz, 1H), 8.77 (s, 1H), 8.47-8.14 (m, 2H), 7.84-7.43 (m, 4H), 5.13(p, J = 6.6 Hz, 1H), 4.48-4.05 (m, 1H), 4.02-3.48 (m, 6H), 3.34 (dddd, J= 34.6, 25.8, 15.6, 10.9 Hz, 4H), 3.09-2.66 (m, 6H), 2.56-2.36 (m, 4H),2.03-1.32 (m, 15H), 1.26-1.00 (m, 6H). 27 691.4 1H NMR (400 MHz,DMSO-d6) delta 10.46 (s, 1H), 9.52 (s, 0.5 1H), 8.87 (d, J = 5.1 Hz,1H), 8.76 (s, 1H), 8.41-8.31 (m, 2H), 7.83-7.75 (m, 1H), 7.70-7.58 (m,3H), 5.13 (p, J = 6.6 Hz, 1H), 4.31 (t, J = 8.2 Hz, 1H), 3.92 (s, 4H),3.44 (dd, J = 34.0, 9.9 Hz, 3H), 2.96 (q, J = 9.7 Hz, 2H), 2.84 (d, J =10.0 Hz, 5H), 1.92- 1.56 (m, 8H), 1.53 (d, J = 6.6 Hz, 7H), 1.42 (t, J =12.7 Hz, 1H), 1.28 (s, 3H), 0.86 (d, J = 5.0 Hz, 2H), 0.57 (d, J = 1.9Hz, 2H). 28 721.4 1H NMR (400 MHz, DMSO-d6) delta 10.49 (s, 1H), 9.52(s, 0.1 1H), 8.87 (d, J = 5.2 Hz, 1H), 8.74 (s, 1H), 8.39-8.29 (m, 2H),7.77 (dd, J = 7.9, 1.4 Hz, 1H), 7.67-7.57 (m, 3H), 5.11 (p, J = 6.6 Hz,1H), 4.29 (p, J = 8.4 Hz, 1H), 3.96-3.84 (m, 2H), 3.84- 3.69 (m, 2H),3.42 (dd, J = 33.4, 9.9 Hz, 4H), 3.03-2.68 (m, 7H), 2.42 (d, J = 2.5 Hz,6H), 1.83 (d, J = 14.0 Hz, 2H), 1.79- 1.66 (m, 4H), 1.61 (d, J = 13.1Hz, 1H), 1.50 (d, J = 6.6 Hz, 6H), 1.40 (t, J = 12.5 Hz, 1H). 29 665.41H NMR (400 MHz, DMSO-d6) delta 10.69 (s, 1H), 10.46 (s, 0.4 1H), 8.92(d, J = 5.4 Hz, 1H), 8.77 (s, 1H), 8.38 (d, J = 6.6 Hz, 1H), 8.34 (s,1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H), 7.65 (p, J = 6.7, 5.3 Hz, 2H), 7.57(d, J = 7.9 Hz, 1H), 5.11 (p, J = 6.6 Hz, 1H), 4.34 (p, J = 8.4 Hz, 1H),3.98-3.76 (m, 2H), 3.76-3.53 (m, 2H), 3.33 (d, J = 11.0 Hz, 1H), 3.21(s, 1H), 2.96 (dq, J = 18.6, 9.7 Hz, 2H), 2.80 (s, 3H), 2.07 (s, 3H),1.88 (q, J = 7.5, 6.3 Hz, 1H), 1.77 (dq, J = 13.3, 6.7, 5.6 Hz, 2H),1.68 (t, J = 5.9 Hz, 2H), 1.50 (d, J = 6.5 Hz, 6H), 1.12 (d, J = 25.7Hz, 6H). 30 667.4 1H NMR (400 MHz, DMSO-d6) delta 9.07 (d, J = 2.2 Hz,1H), 0.6 8.62 (s, 1H), 8.43 (d, J = 3.4 Hz, 1H), 8.18 (t, J = 2.7 Hz,2H), 8.04 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.61-7.50 (m, 2H), 5.28-5.13 (m, 1H), 4.50 (t, J = 8.3 Hz, 1H), 3.82- 3.69(m, 5H), 3.65 (s, 3H), 2.58 (t, J = 9.0 Hz, 1H), 2.26 (s, 5H), 1.71 (t,J = 6.4 Hz, 5H), 1.55 (dd, J = 15.6, 6.1 Hz, 11H), 1.44 (s, 2H). 31665.4 1H NMR (400 MHz, DMSO-d6) delta 10.72 (s, 1H), 9.77-9.65 1.1 (m,1H), 8.86 (d, J = 5.6 Hz, 1H), 8.78 (s, 1H), 8.38 (s, 1H), 7.78 (dd, J =7.8, 1.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H),7.44 (d, J = 7.5 Hz, 1H), 5.07 (hept, J = 6.5 Hz, 1H), 4.37-4.27 (m,1H), 3.96-3.81 (m, 2H), 3.77-3.67 (m, 2H), 3.49 (p, J = 8.1 Hz, 1H),3.39 (d, J = 11.6 Hz, 2H), 3.06- 2.75 (m, 6H), 2.49 (s, 3H), 2.08 (s,3H), 1.88-1.57 (m, 10H), 1.51 (d, J = 6.6 Hz, 6H), 1.46-1.33 (m, 1H). 32665.4 1H NMR (400 MHz, DMSO-d6) delta 10.29 (s, 1H), 9.53 (s, 0.6 1H),8.82 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H), 8.39-8.28 (m, 2H), 7.78 (d, J =7.9 Hz, 1H), 7.70-7.54 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.31 (p, J =8.4 Hz, 1H), 3.95-3.66 (m, 3H), 3.39 (m, 3H), 3.07-2.80 (m, 4H), 2.71(m, 1H), 2.47 (m, 1H), 2.08 (s, 3H), 1.93-1.58 (m, 8H), 1.52 (dt, J =6.8, 2.0 Hz, 6H), 1.09 (q, J = 14.9, 13.2 Hz, 1H), 0.93 (d, J = 6.4 Hz,3H). 33 665.4 1H NMR (400 MHz, DMSO-d6) delta 10.42 (s, 1H), 10.33- 0.310.13 (m, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.39-8.30 (m, 2H), 7.78 (d, J= 7.6 Hz, 1H), 7.66 (s, 1H), 7.64-7.56 (m, 2H), 5.20- 5.03 (m, 1H),4.43-4.30 (m, 1H), 3.98-3.79 (m, 2H), 3.79- 3.55 (m, 4H), 3.23 (s, 2H),3.04-2.87 (m, 2H), 2.87-2.71 (m, 3H), 2.55-2.34 (m, 2H), 2.08 (s, 3H),1.88-1.75 (m, 2H), 1.74- 1.65 (d, J = 6.7 Hz, 2H), 1.52 (d, J = 6.6 Hz,6H), 1.02-0.83 (m, 6H). 34 679.3 1H NMR (400 MHz, DMSO-d6) delta 10.48(s, 1H), 8.88 (d, J = 0.2 5.2 Hz, 1H), 8.76 (s, 1H), 8.38 (d, J = 6.5Hz, 1H), 8.33 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.69-7.53 (m, 3H), 5.13(p, J = 6.7 Hz, 1H), 4.56-4.49 (m, 2H), 4.24 (p, J = 8.1 Hz, 1H),3.97-3.80 (m, 2H), 3.80-3.65 (m, 2H), 3.66-3.51 (m, 1H), 3.43-3.28 (m,2H), 3.11-2.87 (m, 4H), 2.85-2.72 (m, 2H), 2.08 (s, 3H), 2.06-1.93 (m,4H), 1.90-1.75 (m, 2H), 1.70 (t, J = 5.9 Hz, 2H), 1.53 (d, J = 6.5 Hz,6H). 35 733.4 1H NMR (400 MHz, DMSO-d6) delta 10.34 (s, 1H), 9.51 (s,0.2 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.74 (s, 1H), 8.35 (d, J = 6.4 Hz,1H), 8.31 (s, 1H), 7.86-7.74 (m, 1H), 7.71-7.55 (m, 3H), 5.14 (p, J =6.7 Hz, 1H), 4.87 (dd, J = 18.9, 5.9 Hz, 2H), 4.28 (dt, J = 26.8, 7.3Hz, 3H), 3.93 (d, J = 13.4 Hz, 1H), 3.77 (s, 1H), 3.62- 3.34 (m, 3H),3.18 (d, J = 12.2 Hz, 2H), 3.11-2.63 (m, 6H), 1.99-1.66 (m, 6H), 1.60(s, 3H), 1.53 (d, J = 6.6 Hz, 6H), 1.04 (d, J = 10.4 Hz, 1H), 0.73-0.34(m, 4H). 36 707.4 1H NMR (400 MHz, DMSO-d6) delta 10.58 (s, 1H), 9.62(s, 0.3 1H), 8.90 (d, J = 5.3 Hz, 1H), 8.77 (s, 1H), 8.39 (d, J = 6.5Hz, 1H), 8.34 (s, 1H), 7.80 (dd, J = 7.8, 1.4 Hz, 1H), 7.71-7.49 (m,3H), 5.13 (p, J = 6.6 Hz, 1H), 4.50 (q, J = 6.5 Hz, 1H), 4.27 (p, J =8.3 Hz, 1H), 4.05-3.64 (m, 5H), 3.49 (dt, J = 29.7, 10.4 Hz, 2H), 3.17(t, J = 10.5 Hz, 1H), 3.01 (dq, J = 18.2, 9.5 Hz, 1H), 2.86 (m, 4H),2.75 (d, J = 12.2 Hz, 1H), 1.95-1.62 (m, 6H), 1.53 (dd, J = 6.8, 2.8 Hz,6H), 1.25 (t, J = 6.4 Hz, 3H), 1.04 (d, J = 9.6 Hz, 1H), 0.71-0.32 (m,4H). 37 695.4 1H NMR (400 MHz, Methanol-d4) delta 8.80-8.77 (m, 2H), 0.28.31 (dd, J = 6.8, 1.0 Hz, 1H), 8.24 (s, 1H), 7.89 (dd, J = 7.8, 1.4 Hz,1H), 7.77 (dd, J = 7.7, 6.8 Hz, 1H), 7.72 (s, 1H), 7.46 (s, 1H), 5.15(p, J = 6.6 Hz, 1H), 4.99-4.87 (m, 4H), 4.60 (s, 1H), 4.50 (p, J = 8.4Hz, 1H), 4.00 (s, 1H), 3.89-3.79 (m, 1H), 3.76 (t, J = 12.1 Hz, 2H),3.56-3.32 (m, 4H), 3.22 (s, 3H), 2.95- 2.84 (m, 2H), 2.66 (q, J = 0.5Hz, 3H), 2.37 (s, 2H), 2.16 (d, J = 13.2 Hz, 2H), 1.63 (d, J = 6.7 Hz,6H), 1.18 (s, 4H), 1.14 (s, 3H). 38 709.4 1H NMR (400 MHz, DMSO-d6)delta 11.36-10.83 (m, 1H), 1.4 10.30 (s, 1H), 9.87 (s, 1H), 8.82 (d, J =4.6 Hz, 1H), 8.75 (s, 1H), 8.36 (d, J = 6.3 Hz, 1H), 8.32 (s, 1H), 7.83(d, J = 7.4 Hz, 1H), 7.70-7.57 (m, 2H), 7.31 (s, 1H), 5.15 (p, J = 6.6Hz, 1H), 4.83 (t, J = 6.6 Hz, 2H), 4.80-4.75 (m, 2H), 4.54 (s, 1H),4.35-4.24 (m, 1H), 3.80-3.59 (m, 5H), 3.44 (s, 4H), 3.27 (d, J = 11.3Hz, 2H), 3.03 (q, J = 10.3, 9.7 Hz, 3H), 2.89 (dq, J = 13.0, 7.1, 6.6Hz, 1H), 2.82-2.72 (m, 1H), 2.40-1.73 (m, 6H), 1.53 (dd, J = 6.6, 3.9Hz, 6H), 1.19 (s, 3H), 1.15 (s, 3H). 39 709.4 1H NMR (400 MHz, DMSO-d6)delta 11.41-10.87(m, 1H), 0.6 10.41 (s, 1H), 9.88 (s, 1H), 8.86 (d, J =4.9 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 6.3 Hz, 1H), 8.34 (s, 1H), 7.84(d, J = 7.3 Hz, 1H), 7.70-7.60 (m, 2H), 7.31 (s, 1H), 5.14 (p, J = 6.6Hz, 1H), 4.86- 4.81 (m, 2H), 4.81-4.75 (m, 2H), 4.54 (s, 1H), 4.30 (p, J= 7.3 Hz, 1H), 3.80-3.59 (m, 5H), 3.44 (s, 4H), 3.27 (d, J = 8.5 Hz,2H), 3.03 (q, J = 11.2, 10.0 Hz, 3H), 2.90 (td, J = 12.3, 6.3 Hz, 1H),2.83-2.72 (m, 1H), 2.43-1.73 (m, 6H), 1.53 (dd, J = 6.6, 3.7 Hz, 6H),1.19 (s, 3H), 1.15 (s, 3H). 40 695.4 1H NMR (400 MHz, Methanol-d4) delta8.77 (d, J = 5.4 Hz, 0.6 1H), 8.75 (s, 1H), 8.30 (d, J = 6.8 Hz, 1H),8.22 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.1 Hz, 1H), 7.72(s, 1H), 7.48 (s, 1H), 5.15 (p, J = 6.5 Hz, 1H), 4.93 (p, J = 8.0 Hz,4H), 4.60 (s, 1H), 4.49 (p, J = 8.1 Hz, 1H), 4.00 (s, 1H), 3.89-3.70 (m,4H), 3.50 (d, J = 12.4 Hz, 2H), 3.43-3.12 (m, 5H), 2.90 (dt, J = 11.6,6.7 Hz, 2H), 2.35 (s, 2H), 2.16 (d, J = 14.7 Hz, 2H), 1.62 (d, J = 6.6Hz, 6H), 1.18 (s, 3H), 1.15 (s, 3H). 41 679.4 1H NMR (400 MHz, DMSO-d6)delta 11.5-1.08 (m, 1H), 0.6 10.37 (s, 1H), 9.96 (s, 1H), 8.84 (d, J =5.0 Hz, 1H), 8.75 (s, 1H), 8.44-8.29 (m, 2H), 8.05-7.20 (m, 1H), 7.83(d, J = 7.6 Hz, 1H), 7.70-7.59 (m, 2H), 5.15 (p, J = 6.6 Hz, 1H), 4.80(dt, J = 24.3, 7.2 Hz, 4H), 4.34-4.17 (m, 3H), 3.56-3.25 (m, 7H), 3.03-2.80 (m, 4H), 2.70 (m, 1H), 2.46 (m, 1H), 2.40-1.98 (m, 3H), 1.92-1.70(m, 4H), 1.65 (d, J = 14.1 Hz, 1H), 1.53 (dd, J = 6.7, 2.9 Hz, 6H),1.16-1.02 (m, 1H), 0.95-0.89 (m, 3H). 42 669.3 1H NMR (400 MHz, DMSO-d6)delta 11.30-10.75 (m, 2H), 0.6 10.39 (s, 1H), 8.86 (s, 1H), 8.76 (s,1H), 8.39-8.32 (m, 2H), 8.04-7.25 (m, 1H), 7.84 (s, 1H), 7.68 (s, 1H),7.63 (t, J = 7.0 Hz, 1H), 5.52 (d, J = 52.9 Hz, 1H), 5.20-5.07 (m, 1H),4.86- 4.75 (m, 4H), 4.35 (p, J = 8.3 Hz, 1H), 3.90-3.08 (m, 9H), 2.98(p, J = 9.9 Hz, 2H), 2.87-2.76 (m, 2H), 2.54-2.78 (m, 1H, overlappedwith solvent), 2.45-1.78 (m, 5H), 1.52 (d, J = 6.6 Hz, 6H). 43 683.4 1HNMR (400 MHz, DMSO-d6) delta 11.25-10.80 (m, 1H), 1.1 10.58-10.04 (m,2H), 8.88 (s, 1H), 8.76 (s, 1H), 8.41-8.33 (m, 2H), 8.03-7.24 (m, 1H),7.84 (d, J = 7.4 Hz, 1H), 7.75-7.62 (m, 2H), 5.20-4.89 (m, 2H),4.90-4.44 (m, 5H), 4.29 (p, J = 8.2 Hz, 1H), 3.68-3.16 (m, 7H),3.10-2.92 (m, 4H), 2.92-2.82 (m, 2H), 2.40-1.78 (m, 8H), 1.52 (d, J =6.6 Hz, 6H). 44 665.4 1H NMR (400 MHz, DMSO-d6) delta 11.30-10.80 (m,1H), 1.1 10.65-10.20 (m, 2H), 8.88-8.82 (m, 1H), 8.77-8.73 (m, 1H),8.42-8.29 (m, 2H), 7.87-7.80 (m, 1H), 7.72-7.59 (m, 2H), 7.30 (s, 1H),5.21-5.06 (m, 1H), 4.90-4.45 (m, 5H), 4.40- 4.27 (m, J = 10.5 Hz, 1H),3.73-2.88 (m, 10H), 2.85-2.75 (m, 2H), 2.65-2.55 (m, 1H), 2.38-1.98 (m,7H), 1.53 (d, J = 6.6 Hz, 6H), 1.12-1.03 (m, 3H). 45 693.4 1H NMR (400MHz, DMSO-d6) delta 11.27-10.82 (m, 1H), 0.2 10.39 (s, 1H), 9.40-9.10(m, 1H), 8.88-8.82 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 6.4 Hz, 1H), 8.34(s, 1H), 8.02-7.25 (m, 1H), 7.88-7.80 (m, 1H), 7.70-7.58 (m, 2H),5.23-5.08 (m, 1H), 4.90-4.45 (m, 5H), 4.25 (p, J = 8.1 Hz, 1H),3.65-3.15 (m, 5H), 3.14-2.98 (m, 2H), 2.98-2.76 (m, 3H), 2.75-2.61 (m,2H), 2.40-1.96 (m, 4H), 1.90-1.65 (m, 3H), 1.57-1.43 (m, 7H), 1.42-1.30(m, 1H), 1.06 (s, 3H), 0.98 (s, 3H). 46 669.3 1H NMR (400 MHz, DMSO-d6)delta 11.30-9.90 (m, 2H), 1.1 8.77 (s, 1H), 8.73 (s, 1H), 8.37-8.27 (m,2H), 8.04-7.25 (m, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.64-7.56 (m, 1H),5.52 (d, J = 52.9 Hz, 1H), 5.20-5.10 (m, 1H), 4.86-4.45 (m, 5H), 4.35(p, J = 8.3 Hz, 1H), 3.90-3.08 (m, 9H), 2.98 (p, J = 9.9 Hz, 2H),2.87-2.76 (m, 2H), 2.45-1.78 (m, 6H), 1.53 (d, J = 6.6 Hz, 6H). 47 665.41H NMR (400 MHz, DMSO-d6) delta 11.20-10.85 (m, 1H), 1.6 10.60-10.30 (m,1H), 10.30-10.00 (m, 1H), 8.81-8.75 (m, 1H), 8.73 (s, 1H), 8.34 (d, J =6.1 Hz, 1H), 8.01-7.21 (m, 1H), 7.87-7.79 (m, 1H), 7.67 (s, 1H), 7.61(t, J = 6.9 Hz, 1H), 5.23- 5.06 (m, 1H), 4.90-4.45 (m, 5H), 4.40-4.27(m, 1H), 3.71- 3.00 (m, 8H), 3.00-2.87 (m, 2H), 2.83-2.75 (m, 2H), 2.65-2.55 (m, 1H), 2.38-1.98 (m, 5H), 1.95-1.45 (m, 8H), 1.12- 1.03 (m, 3H).48 701.4 1H NMR (400 MHz, DMSO-d6) delta 11.42-10.70 (m, 2H), 1.5 10.44(s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.76 (s, 1H), 8.41-8.30 (m, 2H),8.05-7.23 (m, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.75- 7.60 (m, 2H), 6.20(t, J = 56.3 Hz, 1H), 5.14 (p, J = 6.7 Hz, 1H), 5.05-4.44 (m, 5H), 4.35(p, J = 8.4 Hz, 1H), 3.77-2.90 (m, 12H), 2.87-2.78 (m, 2H), 2.43-1.77(m, 6H), 1.52 (d, J = 6.7 Hz, 6H). 49 695.4 1H NMR (400 MHz, DMSO-d6)delta 10.53 (s, 1H), 8.89 (d, J = 0.5 5.2 Hz, 1H), 8.77 (s, 1H),8.43-8.30 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.74-7.58 (m, 2H), 7.31 (s,1H), 5.14 (p, J = 6.7 H, 1H), 5.02-4.45 (m, 6H), 4.37 (p, J = 8.3 Hz,1H),4.20-3.10 (m, 9H), 2.99 (p, J = 9.9 Hz, 2H), 2.92-2.77 (m, 2H),2.43-1.75 (m, 4H), 1.52 (d, J = 6.6 Hz, 6H), 1.10-0.76 (m, 4H). 50 693.41H NMR (400 MHz, DMSO-d6) delta 11.22-10.70 (m, 1H), 0.5 10.55-10.19 (m,2H), 8.85 (s, 1H), 8.76 (s, 1H), 8.40-8.28 (m, 2H), 8.04-7.26 (m, 1H),7.86 (s, 1H), 7.70-7.55 (m, 2H), 5.21-5.05 (m, 1H), 4.94-4.40 (m, 5H),4.21-4.10 (m, 1H), 4.01- 3.80 (m, 4H), 3.80-3.66 (m, 2H), 3.67-3.08 (m,5H), 3.02- 2.86 (m, 4H), 2.43-1.76 (m. 8H), 1.52 (d, J = 6.6 Hz, 6H). 51569.4 1H NMR (400 MHz, DMSO-d6) delta 10.63 (s, 1H), 9.53 (s, 13.2 1H),8.93 (d, J = 5.3 Hz, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.79 (s, 1H),8.46-8.37 (m, 2H), 7.95 (d, J = 1.8 Hz, 1H), 7.78-7.67 (m, 1H),5.18-5.10 (m, 1H), 4.38-4.24 (m, 1H), 3.56-3.45 (m, 1H), 3.40 (d, J =12.0 Hz, 2H), 3.00-2.75 (m, 4H), 1.85 (d, J = 14.3 Hz, 3H), 1.76-1.57(m, 4H), 1.53 (d, J = 6.6 Hz, 6H), 1.44-1.36 (m, 1H), 1.31 (s, 6H). 52572.2 1H NMR (400 MHz, Methanol-d4) delta 8.78-8.71 (m, 2H), 1.68.33-8.28 (m, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 7.8, 1.6 Hz,1H), 7.75 (dd, J = 8.3, 6.4 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.41 (d,J = 7.8 Hz, 1H), 5.19-5.08 (m, 1H), 4.60 (dd, J = 8.9, 6.9 Hz, 1H),3.76-3.66 (m, 1H), 3.07-3.00 (m, 4H), 2.98 (s, 2H), 1.62 (dd, J = 6.8,2.0 Hz, 6H), 1.40 (d, J = 2.1 Hz, 6H), 1.34 (d, J = 2.0 Hz, 6H). 53586.3 1H NMR (400 MHz, DMSO-d6) delta 10.52 (s, 1H), 8.81 (d, J = 2.15.3 Hz, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 7.78 (dd, J =7.7, 1.4 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.44 (q, J = 7.4 Hz, 1H),5.11-5.01 (m, 1H), 4.35 (s, 1H), 2.96 (dd, J = 9.1, 2.8 Hz, 2H),2.89-2.78 (m, 3H), 1.51 (d, J = 6.6 Hz, 4H), 1.31 (s, 4H), 1.22 (s, 4H).54 582.3 1H NMR (400 MHz, DMSO-d6) delta 10.55 (s, 1H), 9.49(s, 1.5 1H),8.82 (d, J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.35 (s, 1H), 7.79 (dd, J = 7.7,1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 7.8, 6.5 Hz, 2H),5.08 (p, J = 6.6 Hz, 1H), 4.33 (tt, J = 9.2, 7.3 Hz, 2H), 3.41 (d, J =12.2 Hz, 3H), 2.98 (qd, J = 9.1, 2.4 Hz, 3H), 2.93-2.75 (m, 5H), 1.86(d, J = 13.8 Hz, 2H), 1.77-1.56 (m, 4H), 1.52 (d, J = 6.6 Hz, 6H), 1.41(d, J = 12.4 Hz, 1H), 1.31 (s, 6H). 55 570.3 1H NMR (400 MHz, DMSO-d6) 610.46 (s, 1H), 9.51-9.39 (m, 0.9 1H), 8.87 (d, J = 5.2 Hz, 1H), 8.75 (s,1H), 8.38 (d, J = 6.5 Hz, 1H), 8.33 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H),7.65 (t, J = 7.1 Hz, 1H), 7.62 (s, 2H), 7.43 (d, J = 7.7 Hz, 1H), 5.13(p, J = 6.6 Hz, 1H), 4.26 (p, J = 8.5 Hz, 1H), 3.53-3.35 (m, 3H),3.03-2.75 (m, 6H), 1.85 (d, J = 14.1 Hz, 2H), 1.73 (d, J = 13.1 Hz, 1H),1.62 (q, J = 13.1 Hz, 2H), 1.52 (dd, J = 6.6, 2.8 Hz, 6H), 1.47- 1.34(m, 4H).  55A 570.3 1H NMR (400 MHz, DMSO-d6, 1 drop TFA added) delta9.55- 1.2 (1^(st) 9.44 (m, 1H), 8.99 (d, J = 5.6 Hz, 1H), 8.86 (s, 1H),8.43 (d, J = eluting 6.8 Hz, 1H), 8.39 (s, 1H), 7.81 (dd, J = 7.7, 1.4Hz, 1H), 7.70 peak) (dd, J = 7.9, 6.8 Hz, 1H), 7.63 (d, J = 1.4 Hz, 1H),7.44 (d, J = 7.7 Hz, 1H), 5.12 (p, J = 6.6 Hz, 1H), 4.28 (p, J = 8.7 Hz,1H), 3.53-3.36 (m, 3H), 3.04-2.75 (m, 6H), 1.85 (d, J = 14.1 Hz, 2H),1.73 (d, J = 12.9 Hz, 1H), 1.63 (q, J = 12.2, 11.1 Hz, 2H), 1.52 (dd, J= 6.7, 2.8 Hz, 6H), 1.42 (s, 4H).  55B 570.3 1H NMR (400 MHz, DMSO-d6)delta 10.49 (s, 1H), 9.53-9.42 2.2 (2^(nd) (m, 1H), 8.88 (d, J = 5.2 Hz,1H), 8.76 (s, 1H), 8.38 (d, J = 6.5 eluting Hz, 1H), 8.34 (s, 1H), 7.80(dd, J = 7.8, 1.2 Hz, 1H), 7.65 (t, J = peak) 7.1 Hz, 1H), 7.62 (s, 1H),7.43 (d, J = 7.7 Hz, 1H), 5.13 (p, J = 6.7 Hz, 1H), 4.26 (p, J = 8.1 Hz,1H), 3.53-3.35 (m, 3H), 3.02- 2.75 (m, 6H), 1.85 (d, J = 14.0 Hz, 2H),1.73 (d, J = 12.8 Hz, 1H), 1.62 (q, J = 13.1 Hz, 2H), 1.52 (dd, J = 6.6,2.8 Hz, 6H), 1.42 (s, 4H). 56 580.3 1H NMR (400 MHz, DMSO-d6) delta10.44 (s, 1H), 10.31 (s, 0.8 1H), 8.83 (d, J = 4.9 Hz, 1H), 8.74 (s,1H), 8.35 (d, J = 6.4 Hz, 1H), 8.29 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H),7.68-7.60 (m, 2H), 7.43 (d, J = 7.7 Hz, 1H), 5.13 (p, J = 6.7 Hz, 1H),4.37 (p, J = 8.5 Hz, 1H), 3.78-3.60 (m, 2H), 3.37-3.20 (m, 2H),3.20-3.08 (m, 1H), 3.02-2.90 (m, 2H), 2.87-2.74 (m, 2H), 2.14-2.02 (m,1H), 1.96-1.85 (m, 1H), 1.52 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H),0.79-0.68 (m, 3H), 0.68-0.55 (m, 1H). 57 582.3 1H NMR (400 MHz, DMSO-d6)delta 10.30-10.08 (m, 2H), 0.4 8.79 (s, 1H), 8.72 (s, 1H), 8.34 (d, J =6.3 Hz, 1H), 8.27 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67-7.58 (m, 2H),7.43 (d, J = 7.7 Hz, 1H), 5.13 (p, J = 6.7 Hz, 1H), 4.40-4.28 (m, 1H),3.75-3.57 (m, 2H), 3.32-3.16 (m, 2H), 2.98-2.88 (m, 2H), 2.84-2.73 (m,3H), 2.54-2.31 (m, 2H), 1.52 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H),1.01-0.82 (m, 6H). 58 594.4 1H NMR (400 MHz, Chloroform-d) delta 11.21(s, 1H), 8.54- 0.7 8.42 (m, 2H), 8.26 (d, J = 6.5 Hz, 1H), 8.06 (s, 1H),7.93 (t, J = 6.9 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.60 (dd, J = 7.7,1.3 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 5.18 (p, J = 6.6Hz, 1H), 4.59 (p, J = 8.6 Hz, 1H), 3.64 (dd, J = 21.8, 14.0 Hz, 4H),3.39-3.23 (m, 2H), 3.11 (q, J = 9.8 Hz, 1H), 2.93-2.59 (m, 4H),2.28-1.99 (m, 4H), 1.83-1.61 (m, 13H), 1.32 (d, J = 62.2 Hz, 7H). 59582.3 1H NMR (400 MHz, DMSO-d6) delta 10.37 (s, 1H), 9.57 (s, 0.09 1H),8.85 (d, J = 5.0 Hz, 1H), 8.74 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 8.30(s, 1H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.71-7.57 (m, 2H), 7.43 (d, J =7.7 Hz, 1H), 5.13 (p, J = 6.7 Hz, 1H), 4.24 (p, J = 8.3 Hz, 1H), 3.62(q, J = 8.1 Hz, 1H), 3.34 (d, J = 8.8 Hz, 2H), 3.11-2.79 (m, 4H),2.01-1.56 (m, 9H), 1.53 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H). 60 594.3 1HNMR (400 MHz, DMSO-d6) delta 10.37 (d, J = 301.0 Hz, 0.3 1H), 10.29 (s,1H), 8.83 (d, J = 4.9 Hz, 1H), 8.73 (s, 1H), 8.41- 8.20 (m, 2H), 7.78(d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.0 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H),5.13 (p, J = 6.6 Hz, 1H), 4.29 (s, 1H), 3.75 (d, J = 74.2 Hz, 2H), 3.48(s, 1H), 3.31 (s, 1H), 2.98-2.62 (m, 6H), 1.79 (d, J = 19.4 Hz, 2H),1.53 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H), 1.11 (d, J = 32.3 Hz, 5H). 61566.3 1H NMR (400 MHz, DMSO-d6) delta 10.45-10.20 (m, 1H), 0.8 9.85-9.67(m, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 8.29 (s,1H), 7.79 (d, J = 7.8 Hz, 1H), 7.66-7.59 (m, 2H), 7.43 (d, J = 7.8 Hz,1H), 5.13 (p, J = 6.7 Hz, 1H), 4.31 (p, J = 8.3 Hz, 1H), 3.75-3.64 (m,1H), 3.64-3.51 (m, 2H), 3.40- 3.23 (m, 2H), 3.03-2.89 (m, 2H), 2.86-2.71(m, 2H), 1.90- 1.75 (m, 2H), 1.53 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H),0.78-0.68 (m, 1H), 0.69-0.60 (m, 1H). 62 594.3 1H NMR (400 MHz, DMSO-d6)delta 10.52-10.40 (m, 1H), 0.05 9.05-8.91 (m, 1H), 8.88 (d, J = 5.2 Hz,1H), 8.75 (s, 1H), 8.38 (d, J = 6.5 Hz, 1H), 8.30 (s, 1H), 7.80 (dd, J =7.7, 1.4 Hz, 1H), 7.66 (t, J = 7.1 Hz, 1H), 7.59 (d, J = 1.4 Hz, 1H),7.44 (d, J = 7.7 Hz, 1H), 5.13 (p, J = 6.6 Hz, 1H), 4.22 (p, J = 8.3 Hz,1H), 3.61- 3.48 (m, 1H), 3.33-3.25 (m, 2H), 3.04-2.89 (m, 4H), 2.83-2.74 (m, 2H), 2.44-2.37 (m, 2H), 1.81-1.66 (m, 5H), 1.57- 1.45 (m, 7H),1.31 (s, 6H). 63 578.6 1H NMR (400 MHz, DMSO-d6) delta 10.60 (s, 1H),9.59 (d, J = 0.3 8.0 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H),8.40 (d, J = 6.6 Hz, 1H), 8.32 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.68(t, J = 7.2 Hz, 1H), 7.62 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 5.13 (p, J= 6.7 Hz, 1H), 4.35-4.20 (m, 1H), 3.48 (d, J = 7.7 Hz, 1H), 2.99- 2.80(m, 3H), 1.52 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H). 64 574.2 1H NMR (400MHz, Methanol-d4) delta 8.75 (dd, J = 5.5, 1.0 1.3 Hz, 1H), 8.73 (d, J =2.1 Hz, 1H), 8.33-8.26 (m, 1H), 8.20 (d, J = 2.3 Hz, 1H), 7.84 (dt, J =7.8, 1.6 Hz, 1H), 7.75 (dd, J = 8.3, 6.3 Hz, 1H), 7.68 (d, J = 1.6 Hz,1H), 7.41 (d, J = 7.8 Hz, 1H), 5.21-5.08 (m, 1H), 4.65-4.53 (m, 1H),3.76 (td, J = 7.6, 2.2 Hz, 1H), 3.26 (s, 1H), 3.04 (td, J = 7.8, 2.2 Hz,4H), 1.62 (dd, J = 6.8, 2.2 Hz, 6H), 1.56 (d, J = 2.2 Hz, 3H), 1.51 (d,J = 2.3 Hz, 3H), 1.40 (d, J = 2.4 Hz, 6H). 65 586.3 1H NMR (400 MHz,DMSO-d6) delta 9.53 (d, J = 8.4 Hz, 1H), 0.7 9.25 (s, 1H), 8.90 (s, 1H),8.53 (s, 2H), 8.05 (s, 1H), 7.63 (dd, J = 7.7, 1.5 Hz, 1H), 7.41-7.34(m, 2H), 5.45-5.30 (m, 1H), 4.16-4.03 (m, 1H), 3.57-3.42 (m, 1H), 3.38(d, J = 11.9 Hz, 2H), 2.90-2.76 (m, 3H), 2.74-2.62 (m, 2H), 1.92-1.83(m, 2H), 1.77-1.59 (m, 3H), 1.57 (d, J = 6.6 Hz, 6H), 1.51-1.36 (m, 1H),1.27 (s, 6H) 66 580 1H NMR (400 MHz, Methanol-d4) delta 8.81-8.70 (m,2H), 0.7 8.31 (dd, J = 6.7, 1.0 Hz, 1H), 8.21 (s, 1H), 7.87 (dd, J =7.8, 1.4 Hz, 1H), 7.76 (dd, J = 7.7, 6.7 Hz, 1H), 7.69 (d, J = 1.5 Hz,1H), 7.44 (d, J = 7.8 Hz, 1H), 5.16 (p, J = 6.7 Hz, 1H), 4.58-4.49 (m,1H), 4.25-4.05 (m, 2H), 3.76-3.65 (m, 1H), 3.41 (d, J = 11.1 Hz, 1H),3.16-2.93 (m, 4H), 2.85-2.75 (m, 1H), 2.13-1.74 (m, 6H), 1.64 (d, J =6.7 Hz, 6H), 1.42 (s, 6H). 67 651.4 1H NMR (400 MHz, DMSO-d6) delta10.69 (s, 1H), 9.65 (s, 0.5 1H), 8.92 (d, J = 5.4 Hz, 1H), 8.77 (s, 1H),8.42-8.36 (m, 1H), 8.34 (s, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H),7.69-7.63 (m, 2H), 7.57 (d, J = 7.9 Hz, 1H), 5.11 (p, J = 6.7 Hz, 1H),4.28 (p, J = 8.4 Hz, 1H), 3.95-3.64 (m, 4H), 3.42 (dd, J = 33.4, 9.9 Hz,3H), 3.02-2.71 (m, 6H), 2.06 (s, 3H), 1.88-1.29 (m, 15H). 68 699.4 1HNMR (400 MHz, DMSO-d6) delta 9.48 (s, 1H), 8.76 (s, 1H), 0.1 8.64 (s,1H), 8.17 (dt, J = 9.6, 7.9 Hz, 1H), 7.87 (d, J = 3.8 Hz, 1H), 7.64-7.45(m, 2H), 7.40 (d, J = 5.7 Hz, 1H), 7.23 (dd, J = 8.3, 2.8 Hz, 1H), 5.27(p, J = 6.6 Hz, 1H), 4.47 (q, J = 6.5 Hz, 1H), 4.15 (t, J = 8.4 Hz, 1H),4.02-3.62 (m, 4H), 3.44 (dd, J = 26.8, 10.1 Hz, 3H), 3.03-2.70 (m, 7H),1.92-1.62 (m, 9H), 1.59 (d, J = 6.5 Hz, 7H), 1.42 (t, J = 12.6 Hz, 1H),1.22 (t, J = 6.5 Hz, 3H). 69 669.4 1H NMR (400 MHz, DMSO-d6) delta 9.48(d, J = 10.1 Hz, 1H), 5.6 8.73 (s, 1H), 8.20 (d, J = 2.6 Hz, 1H),8.00-7.83 (m, 1H), 7.61 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 1.2 Hz, 1H),5.31 (s, 1H), 4.24 (t, J = 8.1 Hz, 0H), 3.79 (dtd, J = 56.7, 14.2, 13.7,6.7 Hz, 3H), 3.54-3.27 (m, 3H), 3.02-2.71 (m, 7H), 2.06 (s, 3H), 1.91-1.33 (m, 14H). 70 669.4 1H NMR (400 MHz, DMSO-d6) delta 9.49 (d, J = 9.1Hz, 1H), 0.1 8.76 (s, 1H), 8.65 (s, 1H), 8.16 (ddd, J = 9.6, 8.3, 7.3Hz, 1H), 7.86 (s, 1H), 7.58 (dd, J = 7.9, 1.5 Hz, 1H), 7.52 (d, J = 7.9Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.25-7.21 (m, 1H), 5.27 (p, J = 6.6Hz, 1H), 4.15 (q, J = 7.7 Hz, 1H), 3.70 (dq, J = 12.0, 5.8 Hz, 2H), 3.44(dd, J = 26.4, 10.0 Hz, 3H), 3.03-2.68 (m, 3H), 2.11- 2.02 (m, 4H),1.89-1.52 (m, 12H), 1.41 (d, J = 12.2 Hz, 1H). 71 624.4 1H NMR (400 MHz,DMSO-d6) delta 10.48 (d, J = 82.7 Hz, 0.2 2H), 8.89 (d, J = 5.1 Hz, 1H),8.76 (d, J = 2.1 Hz, 1H), 8.38 (dd, J = 6.6, 3.2 Hz, 1H), 8.33 (s, 1H),7.81-7.76 (m, 1H), 7.68- 7.60 (m, 3H), 5.11 (p, J = 6.6 Hz, 1H), 4.34(p, J = 8.4 Hz, 1H), 4.04 (dt, J = 11.6, 5.6 Hz, 2H), 3.83 (dt, J =10.8, 5.1 Hz, 2H), 3.68-3.55 (m, 2H), 3.38-3.15 (m, 2H), 2.96 (d, J =10.3 Hz, 2H), 2.79 (s, 3H), 1.88 (t, J = 7.4 Hz, 1H), 1.76 (q, J = 7.3,6.2 Hz, 5H), 1.50 (d, J = 6.6 Hz, 7H), 1.13 (d, J = 25.4 Hz, 7H). 72665.4 1H NMR (400 MHz, DMSO-d6) delta 10.67 (s, 1H), 9.58 (s, 0.7 1H),8.90 (d, J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.35 (d, J = 6.1 Hz, 2H),7.79-7.75 (m, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H),4.89 (p, J = 6.8 Hz, 1H), 4.30 (q, J = 8.2 Hz, 1H), 3.96-3.78 (m, 1H),3.70 (dd, J = 12.9, 6.3 Hz, 2H), 3.55-3.31 (m, 3H), 3.03-2.72 (m, 6H),2.07 (s, 3H), 1.89-1.48 (m, 13H), 1.39 (t, J = 12.6 Hz, 1H), 0.69-0.62(m, 3H). 73 685.3 1H NMR (400 MHz, DMSO-d6) delta 9.63 (s, 1H), 8.68 (t,J = 0.2 13.4 Hz, 2H), 8.23 (q, J = 8.3 Hz, 1H), 7.86 (d, J = 3.6 Hz,1H), 7.61-7.46 (m, 2H), 7.40 (d, J = 5.5 Hz, 1H), 7.24 (ddd, J = 8.3,2.8, 1.3 Hz, 1H), 4.66 (tt, J = 9.8, 4.7 Hz, 2H), 4.47 (q, J = 6.5 Hz,1H), 4.21-4.07 (m, 1H), 3.80 (td, J = 38.8, 37.0, 14.5 Hz, 5H), 3.44(dd, J = 29.4, 10.1 Hz, 3H), 3.01-2.69 (m, 6H), 1.90- 1.52 (m, 10H),1.46 (td, J = 7.1, 1.9 Hz, 4H), 1.22 (t, J = 6.7 Hz, 3H). 74 736.4 1HNMR (400 MHz, DMSO-d6) delta 9.38 (s, 2H), 8.69 (d, J = 6.6 3.0 Hz, 1H),8.51-8.48 (m, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 7.1, 1.3 Hz,1H), 8.15 (s, 1H), 7.76-7.72 (m, 1H), 7.60 (s, 1H), 7.55 (d, J = 7.8 Hz,1H), 5.26-5.13 (m, 1H), 4.24 (q, J = 8.4 Hz, 1H), 4.12-3.99 (m, 1H),3.85 (td, J = 13.8, 5.3 Hz, 2H), 3.70 (dd, J = 13.3, 7.1 Hz, 2H), 3.37(dd, J = 23.6, 10.4 Hz, 3H), 2.99-2.69 (m, 7H), 2.06 (s, 4H), 1.86-1.55(m, 10H), 1.55- 1.47 (m, 6H), 1.39 (t, J = 12.3 Hz, 1H), 1.16 (d, J =6.6 Hz, 6H). 75 679 1H NMR (400 MHz, Methanol-d4) delta 8.56 (s, 1H),8.35 (d, 0.4 J = 3.6 Hz, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.97 (s, 1H),7.81-7.68 (m, 3H), 7.53 (d, J = 7.9 Hz, 1H), 5.24-5.16 (m, 1H), 4.74 (t,J = 6.7 Hz, 2H), 4.67 (t, J = 6.3 Hz, 2H), 4.34-4.22 (m, 1H), 3.76-3.67(m, 1H), 3.01-2.54 (m, 10H), 2.40 (s, 2H), 2.01-1.80 (m, 4H), 1.70-1.56(m, 8H), 1.08 (s, 6H). 76 707 1H NMR (400 MHz, Methanol-d4) delta8.79-8.73 (m, 2H), 0.5 8.35-8.25 (m, 1H), 8.23-8.19 (m, 1H), 7.87-7.61(m, 3H), 7.58-7.48 (m, 1H), 5.18-5.09 (m, 1H), 4.99-4.86 (m, 4H),4.57-4.47 (m, 1H), 4.30-4.07 (m, 2H), 3.97-3.59 (m, 5H), 3.58-3.36 (m,3H), 3.26-3.10 (m, 2H), 2.98-2.82 (m, 2H), 2.08-1.79 (m, 6H), 1.62 (d, J= 6.7, 6H), 1.24 (s, 6H). 77 721 1H NMR (400 MHz, Methanol-d4) delta8.77-8.72 (m, 2H), 0.4 8.31-8.26 (m, 1H), 8.23-8.19 (m, 1H), 7.87-7.82(m, 1H), 7.74 (t, J = 7.3 Hz, 1H), 7.68 (s, 1H), 7.58-7.54 (m, 1H),5.17- 5.09 (m, 1H), 5.01 (t, J = 6.0 Hz, 2H), 4.56-4.48 (m, 1H), 4.40(t, J = 6.0 Hz, 2H), 4.15-4.05 (m, 1H), 3.93-3.68 (m, 4H), 3.27-3.11 (m,4H), 2.91 (d, J = 9.7 Hz, 4H), 2.04-1.86 (m, 6H), 1.72 (s, 3H), 1.62 (d,J = 6.7 Hz, 6H), 1.24 (s, 6H). 78 707 1H NMR (400 MHz, Methanol-d4)delta 8.79-8.67 (m, 2H), 0.7 8.28 (d, J = 6.8 Hz, 1H), 8.20 (s, 1H),7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.78-7.64 (m, 2H), 7.58-7.46 (m, 1H),5.60-5.52 (m, 1H), 5.13 (p, J = 6.6 Hz, 1H), 4.75-4.67 (m, 1H),4.62-4.49 (m, 2H), 4.25-3.53 (m, 9H), 3.25-3.10 (m, 2H), 3.00-2.85 (m,4H), 2.02-1.79 (m, 6H), 1.61 (d, J = 6.6 Hz, 6H), 1.24 (s, 6H).  78A 7071H NMR (400 MHz, Methanol-d4) delta 8.55 (s, 1H), 8.35 (d, 0.3 (1^(st) J= 3.5 Hz, 1H), 8.15 (d, J = 5.5 Hz, 1H), 7.98-7.85 (m, 1H), eluting7.86-7.67 (m, 3H), 7.48 (dd, J = 24.2, 7.8 Hz, 1H), 5.57-5.47 (m, peak)1H), 5.25-5.14 (m, 1H), 4.74-4.65 (m, 1H), 4.62-4.52 (m, 1H), 4.33-4.22(m, 1H), 4.16-3.70 (m, 4H), 3.65-3.50 (m, 1H), 3.05-2.84 (m, 3H),2.80-2.55 (m, 5H), 2.43 (s, 2H), 2.00-1.70 (m, 6H), 1.64 (dd, J = 9.9,6.9 Hz, 6H), 1.08 (s, 6H).  78B 707 1H NMR (400 MHz, Methanol-d4) delta8.55 (s, 1H), 8.34 (d, 0.3 (2^(nd) J = 3.5 Hz, 1H), 8.15 (d, J = 5.4 Hz,1H), 7.98-7.94 (n, 1H), eluting 7.83-7.67 (m, 3H), 7.47 (dd, J = 24.6,7.8 Hz, 1H), 5.56-5.47 (m, peak) 1H), 5.28-5.11 (m, 1H), 4.75-4.62 (m,1H), 4.62-4.52 (m, 1H), 4.31-4.21 (m, 1H), 4.16-3.75 (m, 4H), 3.64-3.51(m, 1H), 3.02-2.86 (m, 3H), 2.79-2.52 (m, 5H), 2.41 (s, 2H), 1.95-1.70(m, 6H), 1.63 (d, J = 6.6 Hz, 6H), 1.08 (s, 6H). 79 683 1H NMR (400 MHz,Methanol-d4) delta 8.75-8.68 (m, 2H), 0.4 8.27 (d, J = 6.6 Hz, 1H), 8.19(s, 1H), 7.92-7.87 (m, 1H), 7.77- 7.65 (m, 2H), 7.55-7.43 (m, 1H),5.20-5.11 (m, 1H), 5.02- 4.85 (m, 4H), 4.63-4.54 (m, 1H), 4.52-4.42 (m,1H), 3.80- 3.60 (m, 4H), 3.56-3.44 (m, 2H), 3.25-2.89 (m, 8H), 2.37-1.91 (m, 8H), 1.62 (d, J = 6.7 Hz, 6H). 80 697 1H NMR (400 MHz,Methanol-d4) delta 8.83-8.72 (m, 2H), 0.4 8.33 (dd, J = 6.8, 1.0 Hz,1H), 8.23 (s, 1H), 7.93-7.85 (m, 1H), 7.83-7.75 (m, 1H), 7.70 (s, 1H),7.48 (s, 1H), 5.23-5.04 (m, 1H), 5.00-4.90 (m, 4H), 4.67-4.40 (m, 2H),3.78-3.45 (m, 6H), 3.26-2.81 (m, 6H), 2.50-1.87 (m, 8H), 1.84-1.67 (m,1H), 1.62 (dd, J = 6.6, 1.3 Hz, 6H), 1.48 (dd, J = 21.3, 1.9 Hz, 3H). 81608.4 1H NMR (400 MHz, DMSO-d6) delta 9.01-8.86 (m, 1H), 8.79 0.2 (s,1H), 8.14 (s, 1H), 7.77-7.68 (m, 4H), 7.53 (d, J = 1.4 Hz, 1H), 7.40 (d,J = 7.8 Hz, 1H), 6.63-6.54 (m, 1H), 5.34-5.20 (m, 1H), 4.10 (dd, J =9.2, 7.0 Hz, 1H), 3.55 (d, J = 8.2 Hz, 1H), 3.46-3.36 (m, 1H), 3.12 (dd,J = 24.0, 11.4 Hz, 2H), 2.95-2.61 (m, 6H), 1.87-1.67 (m, 3H), 1.61 (dd,J = 6.5, 3.0 Hz, 6H), 1.54-1.33 (m, 2H), 1.29 (d, J = 2.0 Hz, 6H), 1.04(d, J = 27.8 Hz, 7H). 82 594.3 1H NMR (400 MHz, DMSO-d6) delta 8.94 (d,J = 8.8 Hz, 1H), 0.1 8.84 (s, 1H), 8.13 (s, 1H), 7.74-7.68 (m, 4H), 7.53(d, J = 1.4 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H),6.52 (d, J = 9.6 Hz, 1H), 5.31-5.20 (m, 1H), 4.09 (t, J = 8.0 Hz, 1H),3.56 (q, J = 8.1 Hz, 1H), 3.38 (d, J = 11.9 Hz, 1H), 3.13 (d, J = 12.3Hz, 1H), 3.02 (q, J = 9.8 Hz, 1H), 2.96-2.86 (m, 1H), 2.86-2.60 (m, 3H),1.74 (d, J = 9.7 Hz, 3H), 1.59 (d, J = 6.4 Hz, 6H), 1.27 (s, 8H), 1.02(d, J = 28.8 Hz, 6H). 83 568.4 1H NMR (400 MHz, DMSO-d6) delta 10.59 (s,1H), 9.53 (s, 0.8 1H), 8.91 (d, J = 5.3 Hz, 1H), 8.77 (s, 1H), 8.39 (d,J = 6.5 Hz, 1H), 8.33 (s, 1H), 7.80 (dd, J = 7.7, 1.4 Hz, 1H), 7.75-7.61(m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 5.18-5.07 (m, 1H), 4.36-4.23 (m, 1H),3.54-3.43 (m, 1H), 3.44-3.36 (m, 2H), 3.01-2.77 (m, 3H), 1.85 (d, J =14.2 Hz, 2H), 1.64 (ddd, J = 36.1, 25.6, 10.0 Hz, 4H), 1.52 (d, J = 6.6Hz, 6H), 1.47-1.30 (m, 2H), 1.30 (s, 6H). 84 556.4 1H NMR (400 MHz,DMSO-d6) delta 10.69 (s, 1H), 8.93 (d, J = 1.7 5.4 Hz, 1H), 8.84 (s,2H), 8.78 (d, J = 1.2 Hz, 1H), 8.41 (d, J = 6.6 Hz, 1H), 8.34 (s, 1H),7.80 (d, J = 7.8 Hz, 1H), 7.72-7.61 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H),5.19-5.07 (m, 1H), 4.42- 4.29 (m, 1H), 3.59-3.51 (m, 1H), 2.99-2.69 (m,6H), 2.01- 1.86 (m, 1H), 1.53 (d, J = 6.5 Hz, 6H), 1.31 (s, 6H), 0.97(dd, J = 6.8, 1.2 Hz, 6H). 85 554 1H NMR (400 MHz, Methanol-d4) delta8.76 (dd, J = 5.6, 1.0 2.5 Hz, 1H), 8.55 (s, 1H), 8.31 (dd, J = 6.8, 1.0Hz, 1H), 8.18 (s, 1H), 7.88-7.78 (m, 2H), 7.69 (d, J = 1.5 Hz, 1H), 7.40(d, J = 7.8 Hz, 1H), 4.64-4.49 (m, 3H), 3.97 (s, 4H), 3.89-3.82 (m, 1H),3.17-3.07 (m, 2H), 2.89-2.77 (m, 2H), 1.52-1.29 (m, 15H). 86 683 1H NMR(400 MHz, Methanol-d4) delta 8.77-8.68 (m, 2H), 0.6 8.32-8.26 (m, 1H),8.21 (s, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.78-7.67 (m, 2H), 7.48(s, 1H), 5.20-5.09 (m, 1H), 4.92 (p, J = 8.0 Hz, 4H), 4.63-4.44 (m, 2H),3.92-3.38 (m, 9H), 3.28- 3.16 (m, 2H), 2.97-2.83 (m, 2H), 2.54-2.08 (m,6H), 1.72- 1.55 (m, 9H). 87 665 1H NMR (400 MHz, Methanol-d4) delta 8.77(dd, J = 5.6, 1.1 0.7 Hz, 1H), 8.58 (s, 1H), 8.36-8.29 (m, 1H), 8.21 (s,1H), 7.91- 7.82 (m, 2H), 7.72-7.65 (m, 1H), 7.47 (s, 1H), 5.00-4.87 (m,4H), 4.58 (q, J = 7.3 Hz, 3H), 4.53-4.42 (m, 1H), 3.83-3.69 (m, 3H),3.55-2.45 (m, 2H), 3.26-3.15 (m, 2H), 2.96-2.82 (m, 3H), 2.44-1.91 (m,7H), 1.47 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 2.6 Hz, 6H). 88 625.3 1H NMR(400 MHz, DMSO-d6) 6 9.40 (d, J = 29.9 Hz, 2H), 8.2 8.72 (d, J = 21.7Hz, 2H), 8.53 (s, 1H), 8.29 (d, J = 6.9 Hz, 1H), 8.14 (s, 1H), 7.77 (d,J = 7.5 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H), 5.21 (q, J =6.5 Hz, 1H), 4.24 (p, J = 8.3 Hz, 1H), 3.38 (dd, J = 25.2, 10.1 Hz, 3H),2.95-2.66 (m, 9H), 1.90-1.21 (m, 20H). 89 679.4 1H NMR (400 MHz,DMSO-d6) delta 9.81 (s, 1H), 8.87 (s, 1H), 0.5 8.76 (d, J = 3.2 Hz, 1H),8.35 (s, 2H), 7.82 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 25.6 Hz, 2H),4.96-4.70 (m, 6H), 4.32-4.19 (m, 1H), 3.41 (d, J = 38.6 Hz, 9H),3.04-2.65 (m, 7H), 2.39-1.26 (m, 20H), 0.67 (t, J = 7.3 Hz, 3H). 90693.4 1H NMR (400 MHz, DMSO-d6) delta 10.58 (s, 2H), 8.88 (d, J = 0.35.2 Hz, 1H), 8.76 (d, J = 1.0 Hz, 1H), 8.35 (d, J = 6.4 Hz, 2H), 7.82(d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.57 (t, J = 7.1 Hz, 1H), 4.95-4.69(m, 5H), 4.31 (q, J = 8.3 Hz, 1H), 3.75-3.07 (m, 9H), 2.94 (q, J = 10.0Hz, 2H), 2.80 (d, J = 8.4 Hz, 3H), 2.39- 1.68 (m, 7H), 1.56 (d, J = 6.7Hz, 3H), 1.12 (d, J = 26.7 Hz, 6H), 0.67 (t, J = 7.3 Hz, 3H). 91 683.41H NMR (400 MHz, DMSO-d6) delta 11.35-10.87(m, 1H), 0.2 9.94-9.67 (m,1H), 9.58 (s, 1H), 8.72 (s, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.83 (d, J= 5.6 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.60 (s, 1H), 7.39 (t, J = 5.4Hz, 1H), 7.29 (s, 1H), 5.22 (p, J = 6.6 Hz, 1H), 4.80 (dt, J = 25.3, 7.3Hz, 4H), 4.53 (s, 1H), 4.23 (s, 1H), 3.63-3.16 (m, 7H), 2.92 (q, J = 9.2Hz, 2H), 2.82 (q, J = 10.4, 9.4 Hz, 4H), 2.39-1.96 (m, 3H), 1.85 (d, J =13.9 Hz, 2H), 1.76-1.57 (m, 3H), 1.54 (d, J = 6.6 Hz, 6H), 1.48-1.36 (m,1H). 92 683.4 1H NMR (400 MHz, DMSO-d6) delta 10.99 (d, J = 44.4 Hz, 1.91H), 9.70 (d, J = 34.0 Hz, 1H), 9.50 (s, 1H), 8.70 (s, 1H), 8.28- 8.17(m, 1H), 8.15 (d, J = 2.8 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J = 7.6 Hz,1H), 7.64 (s, 1H), 7.27 (s, 1H), 5.19 (p, J = 6.6 Hz, 1H), 4.80 (dt, J =21.1, 7.6 Hz, 4H), 4.52 (s, 1H), 4.26 (s, 1H), 3.65- 3.19 (m, 7H),2.99-2.88 (m, 2H), 2.89-2.76 (m, 4H), 2.39- 1.97 (m, 3H), 1.84 (d, J =14.1 Hz, 2H), 1.76-1.57 (m, 3H), 1.54 (d, J = 6.6 Hz, 6H), 1.48-1.36 (m,1H). 93 697.4 1H NMR (400 MHz, DMSO-d6) delta 11.30-10.90 (m, 1H), 0.210.78-10.47 (m, 1H), 9.58 (s, 1H), 8.72 (s, 1H), 8.26-8.14 (m, 1H), 7.84(d, J = 5.6 Hz, 1H), 7.81 (d, J = 5.1 Hz, 1H), 7.67- 7.55 (m, 1H), 7.39(t, J = 5.4 Hz, 1H), 7.29 (s, 1H), 5.22 (p, J = 6.6 Hz, 1H), 4.83 (t, J= 6.8 Hz, 2H), 4.77 (t, J = 7.4 Hz, 2H), 4.54 (s, 1H), 4.25 (s, 1H),3.74-3.52 (m, 3H), 3.44 (s, 3H), 3.35-3.18 (m, 3H), 2.99-2.72 (m, 5H),2.39-1.97 (m, 3H), 1.92 (dt, J = 14.5, 7.8 Hz, 1H), 1.88-1.73 (m, 2H),1.54 (d, J = 6.6 Hz, 6H), 1.19 (s, 3H), 1.11 (s, 3H). 94 586.4 1H NMR(400 MHz, DMSO-d6) delta 9.61-9.55 (m, 1H), 9.52 0.3 (d, J = 9.5 Hz,1H), 8.78 (s, 1H), 8.16 (s, 1H), 7.84 (dd, J = 5.6, 1.0 Hz, 1H), 7.75(dd, J = 7.8, 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.46-7.36 (m, 2H),5.28-5.16 (m, 1H), 4.29-4.15 (m, 1H), 3.56-3.41 (m, 1H), 3.38 (d, J =11.8 Hz, 2H), 2.97-2.76 (m, 5H), 1.85 (d, J = 14.1 Hz, 2H), 1.76-1.58(m, 3H), 1.54 (d, J = 6.6 Hz, 6H), 1.49-1.35 (m, 1H), 1.29 (s, 6H). 95587.4 1H NMR (400 MHz, DMSO-d6) delta 9.60 (d, J = 2.1 Hz, 1H), 2.5 9.50(d, J = 8.0 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.78 (s, 1H), 8.26 (s,1H), 7.88-7.81 (m, 2H), 7.43 (t, J = 5.5 Hz, 1H), 5.29- 5.17 (m, 1H),4.33-4.19 (m, 1H), 3.59-3.44 (m, 1H), 3.42- 3.34 (m, 2H), 2.94-2.76 (m,5H), 1.85 (d, J = 14.3 Hz, 2H), 1.76-1.58 (m, 3H), 1.55 (d, J = 6.6 Hz,6H), 1.45-1.37 (m, 1H), 1.31 (s, 6H). 96 725.4 1H NMR (400 MHz, DMSO-d6)delta 9.47 (d, J = 10.2 Hz, 1H), 0.2 8.73 (s, 1H), 8.62 (s, 1H), 8.18(q, J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.60 (s, 2H), 7.43 (s, 1H), 7.24 (dd,J = 8.3, 2.8 Hz, 1H), 5.27 (q, J = 6.6 Hz, 1H), 4.86 (dd, J = 22.5, 5.9Hz, 2H), 4.30 (t, J = 5.5 Hz, 2H), 4.25-4.11 (m, 1H), 3.97-3.84 (m, 1H),3.77 (dt, J = 13.3, 6.5 Hz, 1H), 3.47 (dt, J = 30.1, 10.0 Hz, 5H),3.25-3.11 (m, 1H), 3.06-2.75 (m, 6H), 1.90-1.63 (m, 8H), 1.63-1.55 (m,9H), 1.50-1.35 (m, 1H) 97 681.4 1H NMR (400 MHz, DMSO-d6) delta9.50-9.39 (m, 1H), 8.79 0.2 (s, 1H), 8.42-8.35 (m, 1H), 8.26 (d, J =10.5 Hz, 1H), 7.80 (s, 1H), 7.58 (dd, J = 8.0, 1.4 Hz, 1H), 7.52 (d, J =7.9 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H), 6.99 (d, J = 11.4 Hz, 1H), 5.30(p, J = 6.5 Hz, 1H), 4.14 (p, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.91-3.79(m, 2H), 3.77-3.66 (m, 2H), 3.50 (q, J = 7.9 Hz, 1H), 3.42 (d, J = 12.0Hz, 2H), 3.06-2.89 (m, 2H), 2.87-2.73 (m, 4H), 2.07 (s, 3H), 1.91-1.64(m, 9H), 1.62 (d, J = 6.5 Hz, 6H), 1.51-1.35 (m, 1H). 98 681.4 1H NMR(400 MHz, DMSO-d6) delta 10.41 (s, 1H), 9.59-9.48 1.0 (m, 1H), 8.75 (d,J = 6.2 Hz, 2H), 8.32 (s, 1H), 7.79 (dd, J = 8.1, 1.3 Hz, 1H), 7.66-7.61(m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 5.12 (p, J = 6.6 Hz, 1H), 4.62 (s,2H), 4.32 (p, J = 8.2 Hz, 1H), 3.96- 3.81 (m, 2H), 3.78-3.67 (m, 2H),3.52-3.35 (m, 3H), 3.05- 2.90 (m, 2H), 2.89-2.75 (m, 4H), 2.08 (s, 3H),1.89-1.56 (m, 10H), 1.52 (d, J = 6.6 Hz, 6H), 1.47-1.34 (m, 1H). 99694.5 1H NMR (500 MHz, DMSO-d6) delta 9.50 (s, 1H), 8.70 (s, 1H), 1.68.27 (s, 1H), 8.17 (s, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 7.72- 7.53(m, 2H), 6.95 (d, J = 6.4 Hz, 1H), 5.29-5.04 (m, 1H), 4.33 (t, J = 8.2Hz, 1H), 4.05-3.64 (m, 4H), 3.51-3.26 (m, 4H), 3.20-2.65 (m, 12H), 2.08(s, 4H), 1.95-1.30 (m, 15H). 100  598.4 1H NMR (400 MHz, DMSO-d6) delta10.54 (s, 1H), 10.46 (s, 3.1 1H), 8.78-8.74 (m, 2H), 8.31 (s, 1H), 7.79(dd, J = 7.7, 1.4 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.65 (d, J = 7.5Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 5.11 (p, J = 6.6 Hz, 1H), 4.63 (s,2H), 4.46 (p, J = 8.5 Hz, 1H), 3.91-3.73 (m, 6H), 2.94 (dt, J = 12.0,9.0 Hz, 2H), 2.69 (qd, J = 9.7, 8.6, 5.1 Hz, 2H), 1.52 (d, J = 6.6 Hz,6H), 1.35 (s, 3H), 1.31 (s, 6H), 1.25 (s, 3H). 101  588.2 1H NMR (400MHz, Methanol-d4) delta 8.72 (s, 1H), 8.05 (s, 0.3 1H), 7.88-7.77 (m,2H), 7.64 (d, J = 1.4 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.44 (t, J =5.5 Hz, 1H), 5.26 (p, J = 6.7 Hz, 1H), 4.30 (p, J = 8.6 Hz, 1H), 3.57(dd, J = 23.7, 10.4 Hz, 3H), 3.12- 2.98 (m, 2H), 2.98-2.77 (m, 4H), 2.04(d, J = 14.7 Hz, 2H), 1.98-1.86 (m, 1H), 1.77 (q, J = 13.0 Hz, 2H), 1.67(d, J = 6.7 Hz, 6H), 1.56 (s, 4H). 102  699.4 1H NMR (400 MHz,Methanol-d4) delta 8.73 (s, 1H), 8.05 (s, 0.1 1H), 7.81 (t, J = 5.6 Hz,2H), 7.66 (s, 1H), 7.56 (dd, J = 26.1, 7.9 Hz, 1H), 7.44 (t, J = 5.5 Hz,1H), 5.27 (p, J = 6.7 Hz, 1H), 4.67 (d, J = 6.8 Hz, 1H), 4.33 (q, J =8.3 Hz, 1H), 4.24-3.83 (m, 4H), 3.66-3.44 (m, 3H), 3.07 (dt, J = 25.1,12.6 Hz, 2H), 3.01-2.83 (m, 4H), 2.11-1.70 (m, 9H), 1.67 (d, J = 6.7 Hz,6H), 1.58 (d, J = 12.4 Hz, 1H), 1.40 (dd, J = 9.5, 6.5 Hz, 3H). 103 727.3 1H NMR (400 MHz, Methanol-d4) delta 8.72 (s, 1H), 8.04 (s, 0.21H), 7.87-7.76 (m, 2H), 7.67 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 7.9 Hz,1H), 7.44 (t, J = 5.5 Hz, 1H), 5.26 (p, J = 6.7 Hz, 1H), 4.34 (p, J =8.3 Hz, 1H), 4.08 (s, 4H), 3.69-3.47 (m, 5H), 3.08 (dt, J = 11.9, 9.1Hz, 2H), 2.99-2.85 (m, 4H), 2.04 (d, J = 14.6 Hz, 2H), 1.91 (d, J = 6.5Hz, 5H), 1.78 (t, J = 13.4 Hz, 2H), 1.67 (d, J = 6.7 Hz, 6H), 1.58 (d, J= 12.6 Hz, 1H), 1.35 (s, 6H). 104  625.3 1H NMR (400 MHz, DMSO-d6) delta9.45 (s, 1H), 9.25 (s, 1H), 1.4 8.64 (d, J = 8.5 Hz, 1H), 8.16-7.97 (m,2H), 7.94-7.72 (m, 1H), 7.72-7.28 (m, 3H), 5.25 (s, 1H), 4.10 (s, 1H),3.34 (d, J = 12.1 Hz, 3H), 2.96-2.63 (m, 3H), 1.85 (d, J = 14.0 Hz, 3H),1.73 (d, J = 14.0 Hz, 1H), 1.58 (d, J = 9.4 Hz, 10H), 1.48-1.10 (m,10H). 105  701.4 1H NMR (400 MHz, DMSO-d6) delta 9.85 (s, 1H), 9.50-9.380.4 (m, 2H), 8.73 (s, 1H), 8.45 (d, J = 6.5 Hz, 1H), 8.34 (d, J = 11.6Hz, 1H), 8.29 (s, 1H), 8.12 (d, J = 6.7 Hz, 1H), 7.97 (d, J = 7.8 Hz,1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.66 (s, 1H), 7.56 (d, J = 7.9 Hz,1H), 5.18 (p, J = 6.6 Hz, 1H), 4.28 (p, J = 8.5 Hz, 1H), 3.94-3.80 (m,2H), 3.77-3.66 (m , 2H), 3.40-3.27 (m, 3H), 2.96 (dq, J = 20.3, 9.8, 9.3Hz, 2H), 2.83-2.68 (m, 4H), 2.07 (s, 3H), 1.88-1.55 (m, 9H), 1.52 (d, J= 6.6 Hz, 6H), 1.46-1.32 (m, 1H). 106  709.5 1H NMR (400 MHz, DMSO-d6)delta 9.07 (d, J = 2.3 Hz, 1H), 0.3 8.61 (s, 1H), 8.42 (d, J = 3.4 Hz,1H), 8.18 (d, J = 5.1 Hz, 2H), 8.07-8.01 (m, 1H), 7.75 (dd, J = 7.8, 1.4Hz, 1H), 7.60-7.49 (m, 2H), 5.75 (s, 0H), 5.27-5.11 (m, 1H), 4.62-4.43(m, 3H), 3.89 (d, J = 6.2 Hz, 5H), 3.46 (d, J = 5.9 Hz, 2H), 2.69-2.56(m, 2H), 2.26 (s, 5H), 1.72 (d, J = 5.3 Hz, 4H), 1.57 (d, J = 5.4 Hz,2H), 1.53 (d, J = 6.6 Hz, 6H), 1.43 (s, 2H), 1.20 (s, 6H). 107  721.4 1HNMR (400 MHz, DMSO-d6) delta 10.49 (s, 1H), 9.58-9.47 0.3 (m, 1H), 8.88(d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 6.5 Hz, 1H), 8.34 (s,1H), 7.79 (d, J = 7.8 Hz, 1H), 7.68-7.59 (m, 3H), 5.13 (p, J = 6.7 Hz,1H), 4.32 (p, J = 8.6 Hz, 1H), 3.96- 3.75 (m, 4H), 3.48 (q, J = 8.0 Hz,1H), 3.39 (d, J = 11.9 Hz, 2H), 3.12 (s, 3H), 2.97 (h, J = 9.6, 8.5 Hz,2H), 2.88-2.75 (m, 4H), 2.62-2.53 (m, 2H), 2.12 (p, J = 9.2 Hz, 2H),1.89-1.55 (m, 12H), 1.52 (d, J = 6.6 Hz, 6H), 1.46-1.34 (m, 1H). 108 721.4 1H NMR (400 MHz, DMSO-d6) delta 10.32 (s, 1H), 8.95 (s, 0.2 1H),8.83 (d, J = 4.9 Hz, 1H), 8.74 (s, 1H), 8.35 (d, J = 6.4 Hz, 1H), 8.31(s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.65-7.56 (m, 3H), 5.46 (t, J = 7.6Hz, 1H), 5.13 (p, J = 6.4 Hz, 1H), 4.56 (td, J = 8.0, 5.6 Hz, 1H),4.46-4.39 (m, 1H), 4.27 (p, J = 8.3 Hz, 1H), 3.99-3.67 (m, 3H),3.60-3.33 (m, 3H), 3.16-2.99 (m, 2H), 2.99-2.61 (m, 7H), 1.83-1.67 (m,6H), 1.57-1.44 (m, 7H), 1.41-1.31 (m, 1H), 1.07 (s, 3H), 0.99 (s, 3H).109  721.4 1H NMR (400 MHz, DMSO-d6) delta 10.57 (s, 1H), 9.57 (s, 0.31H), 8.90 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.39 (d, J = 6.5 Hz, 1H),8.35 (s, 1H), 7.80 (t, J = 6.9 Hz, 1H), 7.65 (s, 2H), 7.55 (dd, J =22.8, 7.8 Hz, 1H), 5.13 (p, J = 6.6 Hz, 1H), 4.35-4.26 (m, 2H),4.03-3.69 (m, 4H), 3.48 (q, J = 7.9 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H),3.04-2.75 (m, 7H), 2.04 (dt, J = 19.9, 9.2 Hz, 1H), 1.93-1.34 (m, 23H).110  719.4 1H NMR (400 MHz, DMSO-d6) delta 9.05 (d, J = 2.2 Hz, 1H), 0.28.61 (s, 1H), 8.42 (d, J = 3.4 Hz, 1H), 8.17 (d, J = 5.4 Hz, 1H), 8.08(s, 1H), 7.83 (s, 1H), 7.72 (dd, J = 7.9, 1.4 Hz, 1H), 7.63- 7.56 (m,2H), 5.19 (p, J = 6.6 Hz, 1H), 4.86 (dd, J = 14.6, 5.8 Hz, 2H), 4.38 (p,J = 8.7 Hz, 1H), 4.29 (dd, J = 8.2, 5.8 Hz, 2H), 3.97-3.87 (m, 1H),3.80-3.70 (m, 1H), 3.58-3.46 (m, 1H), 3.20-3.10 (m, 1H), 2.81 (p, J =7.4 Hz, 1H), 2.77-2.70 (m, 3H), 2.67 (d, J = 9.1 Hz, 3H), 2.52-2.41 (m,2H), 2.09-1.95 (m, 4H), 1.85-1.68 (m, 4H), 1.66-1.68 (m, 5H), 1.53 (d, J= 6.6 Hz, 6H). 111  719.4 1H NMR (400 MHz, DMSO-d6) delta 10.35 (s, 2H),8.83 (s, 0.08 1H), 8.74 (s, 1H), 8.40-8.28 (m, 2H), 7.80 (d, J = 7.8 Hz,1H), 7.70-7.55 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.74 (dd, J = 7.4, 5.9Hz, 1H), 4.41-4.26 (m, 1H), 4.01-3.51 (m, 9H), 3.21-2.95 (m, 6H),2.87-2.78 (m, 2H), 2.29-1.95 (m, 4H), 1.95-1.77 (m, 6H), 1.77-1.66 (m,2H), 1.52 (d, J = 6.6 Hz, 6H). 112  721.4 1H NMR (400 MHz, DMSO-d6)delta 10.35-10.10(m, 2H), 0.08 8.78 (s, 1H), 8.72 (s, 1H), 8.33 (d, J =6.3 Hz, 1H), 8.30 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.66 (s, 1H),7.63-7.58 (m, 2H), 5.15 (p, J = 6.6 Hz, 1H), 4.34 (p, J = 8.2 Hz, 1H),3.97-3.86 (m, 5H), 3.67-3.56 (m, 2H), 3.47 (s, 2H), 3.20-3.01 (m, 6H),2.86- 2.76 (m, 2H), 2.30-2.16 (m, 2H), 1.87-1.71 (m, 6H), 1.53 (d, J =6.6 Hz, 6H), 1.22 (s, 6H). 113  693.4 1H NMR (400 MHz, DMSO-d6) delta10.36 (s, 2H), 8.84 (s, 0.07 1H), 8.75 (s, 1H), 8.38-8.29 (m, 2H), 7.80(d, J = 8.0 Hz, 1H), 7.70-7.52 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.50(q, J = 6.5 Hz, 1H), 4.34 (p, J = 8.4 Hz, 1H), 4.04-3.69 (m, 4H),3.68-3.56 (m, 3H), 3.20-2.92 (m, 6H), 2.88-2.78 (m, 2H), 2.30-2.12 (m,2H), 1.96-1.65 (m, 6H), 1.52 (d, J = 6.6 Hz, 6H), 1.25 (t, J = 6.2 Hz,3H). 114  695.5 1H NMR (400 MHz, DMSO-d6) delta 10.53 (s, 1H), 9.50 (s,0.4 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.41-8.32 (m, 2H), 7.80(d, J = 7.8 Hz, 1H), 7.69-7.52 (m, 3H), 5.18-5.07 (m, 1H), 4.38-4.24 (m,2H), 4.06-3.72 (m, 4H), 3.51-3.44 (m, 1H), 3.44-3.36 (m, 2H), 3.03-2.91(m, 2H), 2.90-2.77 (m, 4H), 1.93-1.58 (m, 11H), 1.52 (d, J = 6.6 Hz,6H), 1.42 (t, J = 12.5 Hz, 1H), 0.91 (q, J = 7.3 Hz, 3H). 115  695.5 1HNMR (400 MHz, DMSO-d6) delta 10.43 (s, 1H), 9.51 (s, 0.4 1H), 8.86 (d, J= 5.1 Hz, 1H), 8.75 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 8.33 (s, 1H),7.79 (d, J = 7.8 Hz, 1H), 7.69-7.58 (m, 2H), 7.55 (d, J = 7.9 Hz, 1H),5.19-5.07 (m, 1H), 4.37-4.24 (m, 2H), 4.05-3.78 (m, 4H), 3.51-3.44 (m,1H), 3.43-3.35 (m, 2H), 3.02-2.90 (m, 2H), 2.90-2.78 (m, 5H), 1.89-1.58(m, 9H), 1.52 (d, J = 6.6 Hz, 6H), 1.40 (d, J = 12.4 Hz, 2H), 0.91 (q, J= 7.4 Hz, 3H). 116  709.5 1H NMR (400 MHz, DMSO-d6) delta 10.48 (s, 1H),10.33 (s, 0.4 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J =6.5 Hz, 1H), 8.33 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69-7.59 (m, 2H),7.56 (d, J = 7.8 Hz, 1H), 5.19-5.07 (m, 1H), 4.42-4.24 (m, 3H), 3.82(ddt, J = 69.9, 62.5, 19.9 Hz, 5H), 3.42-3.18 (m, 2H), 2.96 (d, J = 12.5Hz, 2H), 2.80 (d, J = 14.2 Hz, 3H), 1.97-1.58 (m, 6H), 1.52 (d, J = 6.6Hz, 6H), 1.49-1.44 (m, 1H), 1.20- 1.09 (m, 7H), 0.96-0.86 (m, 3H). 117 709.5 1H NMR (400 MHz, DMSO-d6) delta 10.34 (s, 1H), 10.24 (s, 0.2 1H),8.84 (d, J = 4.9 Hz, 1H), 8.75 (s, 1H), 8.35 (d, J = 6.3 Hz, 1H), 8.32(s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.69-7.58 (m, 2H), 7.56 (d, J = 7.9Hz, 1H), 5.17-5.09 (m, 1H), 4.43-4.26 (m, 2H), 4.08-3.73 (m, 3H), 3.68(d, J = 7.6 Hz, 2H), 3.44-3.19 (m, 2H), 3.01-2.96 (m, 2H), 2.84-2.79 (m,3H), 1.99-1.60 (m, 8H), 1.53 (d, J = 6.6 Hz, 6H), 1.50-1.46 (m, 1H),1.21- 1.10 (m, 7H), 0.97-0.86 (m, 3H). 118  723.5 1H NMR (400 MHz,DMSO-d6) delta 10.44(s, 2H), 10.25 (s, 0.2 1H), 8.86 (d, J = 5.1 Hz,1H), 8.75 (s, 1H), 8.39-8.31 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H),7.73-7.53 (m, 3H), 5.17-5.07 (m, 1H), 4.43-4.30 (m, 1H), 4.17-4.08 (m,1H), 3.99-3.59 (m, 3H), 3.24 (s, 1H), 2.98 (s, 2H), 2.81 (s, 3H),1.98-1.67 (m, 9H), 1.52 (d, J = 6.6 Hz, 6H), 1.20-1.09 (m, 7H),0.96-0.79 (m, 7H). 119  723.5 1H NMR (400 MHz, DMSO-d6) delta 10.36(s,1H), 10.22 (s, 0.2 1H), 8.84 (d, J = 4.9 Hz, 1H), 8.75 (s, 1H),8.38-8.30 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.74-7.49 (m, 3H),5.19-5.07 (m, 1H), 4.43-4.30 (m, 1H), 4.17-4.08 (m, 1H), 3.85-3.80 (m,2H), 3.43-3.16 (m, 2H), 2.98 (s, 2H), 2.83-2.78 (m, 5H), 2.01-1.70 (m,9H), 1.52 (d, J = 6.6 Hz, 6H), 1.18 (s, 3H), 1.12 (s, 3H), 0.96-0.81 (m,6H). 120  695 1H NMR (400 MHz, Methanol-d4) delta 8.78-8.71 (m, 2H), 0.58.29 (dd, J = 6.8, 1.0 Hz, 1H), 8.21 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H),7.74 (t, J = 7.2 Hz, 1H), 7.68 (s, 1H), 7.57-7.47 (m, 1H), 5.16-5.10 (m,1H), 4.69-4.61 (m, 1H), 4.58-4.48 (m, 1H), 4.22-3.73 (m, 7H), 3.25-3.15(m, 3H), 2.97-2.87 (m, 3H), 2.06-1.80 (m, 6H), 1.62 (d, J = 6.7 Hz, 6H),1.42-1.33 (m, 3H), 1.24 (s, 6H). 121  693.4 1H NMR (400 MHz, DMSO-d6)delta 10.52 (s, 1H), 9.55 (d, J = 0.2 9.2 Hz, 1H), 8.89 (d, J = 5.2 Hz,1H), 8.76 (s, 1H), 8.37 (d, J = 6.6 Hz, 1H), 8.33 (s, 1H), 7.79 (dd, J =7.9, 1.5 Hz, 1H), 7.69- 7.51 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.27 (p,J = 8.3 Hz, 1H), 4.17 (s, 2H), 4.00-3.86 (m, 1H), 3.86-3.71 (m, 2H),3.62 (d, J = 13.9 Hz, 1H), 3.48 (m, 2H), 3.17 (t, J = 10.5 Hz, 1H), 2.99(dt, J = 18.8, 9.4 Hz, 1H), 2.87 (m, 4H), 2.75 (d, J = 12.2 Hz, 1H),1.81 (m, 7H), 1.52 (dd, J = 6.9, 2.3 Hz, 6H), 1.04 (d, J = 10.1 Hz, 1H),0.70-0.31 (m, 3H). 122  735.4 1H NMR (400 MHz, DMSO-d6) delta 10.52 (s,1H), 9.57 (s, 0.2 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.43-8.35(m, 1H), 8.33 (s, 1H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.63 (ddd, J =13.9, 10.1, 7.2 Hz, 3H), 5.13 (p, J = 6.7 Hz, 1H), 4.34-4.19 (m, 1H),3.92 (t, J = 5.2 Hz, 4H), 3.58-3.36 (m, 3H), 3.17 (t, J = 10.5 Hz, 1H),3.01 (q, J = 9.7 Hz, 1H), 2.92-2.78 (m, 5H), 2.74 (d, J = 12.1 Hz, 1H),1.96-1.63 (m, 7H), 1.53 (dd, J = 6.8, 2.4 Hz, 6H), 1.22 (s, 6H), 1.04(d, J = 10.0 Hz, 1H), 0.72-0.34 (m, 3H). 123  733.4 1H NMR (400 MHz,DMSO-d6) delta 10.55 (s, 1H), 9.01 (s, 0.1 1H), 8.90 (d, J = 5.3 Hz,1H), 8.77 (s, 1H), 8.44-8.36 (m, 1H), 8.34 (s, 1H), 7.80 (dd, J = 7.9,1.5 Hz, 1H), 7.73-7.54 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.87 (dd, J =17.8, 5.9 Hz, 2H), 4.36- 4.28 (m, 2H), 4.23 (p, J = 8.3 Hz, 1H), 3.94(d, J = 13.4 Hz, 1H), 3.78 (d, J = 8.2 Hz, 1H), 3.53 (d, J = 11.3 Hz,2H), 3.29 (d, J = 11.7 Hz, 2H), 3.23-3.11 (m, 1H), 2.97 (m, 3H), 2.78(d, J = 9.3 Hz, 2H), 2.40 (s, 2H), 1.72 (d, J = 29.6 Hz, 9H), 1.60 (s,3H), 1.53 (d, J = 6.6 Hz, 7H). 124  719.4 1H NMR (400 MHz, DMSO-d6)delta 10.47 (s, 1H), 8.99 (s, 0.07 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.76(s, 1H), 8.37 (d, J = 6.4 Hz, 1H), 8.32 (s, 1H), 7.79 (dt, J = 7.8, 2.5Hz, 1H), 7.70-7.56 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.81-4.65 (m, 3H),4.20 (tq, J = 8.5, 6.7 Hz, 2H), 3.97 (d, J = 14.1 Hz, 1H), 3.77 (td, J =8.3, 7.8, 4.2 Hz, 1H), 3.69-3.44 (m, 2H), 3.44-3.34 (m, 1H), 3.29 (d, J= 11.8 Hz, 2H), 3.08-2.84 (m, 4H), 2.84-2.69 (m, 2H), 2.43- 2.34 (m,2H), 1.87-1.60 (m, 10H), 1.52 (d, J = 6.6 Hz, 6H). 125  719.4 1H NMR(400 MHz, DMSO-d6) delta 10.63 (s, 1H), 9.14 (s, 0.04 1H), 8.92 (d, J =5.3 Hz, 1H), 8.78 (s, 1H), 8.41 (d, J = 6.5 Hz, 1H), 8.34 (s, 1H), 7.80(dt, J = 7.8, 1.7 Hz, 1H), 7.68 (ddd, J = 7.7, 6.4, 2.6 Hz, 1H), 7.59(q, J = 8.1 Hz, 2H), 5.47 (t, J = 7.6 Hz, 1H), 5.14 (p, J = 6.6 Hz, 1H),4.56 (td, J = 8.0, 5.6 Hz, 1H), 4.43 (dtd, J = 8.3, 5.7, 2.2 Hz, 1H),4.31-4.17 (m, 1H), 4.02- 3.64 (m, 2H), 3.64-3.48 (m, 2H), 3.30(d, J =11.7 Hz, 2H), 3.09-2.84 (m, 3H), 2.84-2.69 (m, 3H), 2.40 (s, 2H), 1.72(d, J = 30.3 Hz, 10H), 1.53 (d, J = 6.6 Hz, 7H). 126  707.4 1H NMR (400MHz, DMSO-d6) delta 10.36 (s, 1H), 8.93 (s, 0.1 1H), 8.84 (d, J = 5.0Hz, 1H), 8.75 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 8.31 (s, 1H), 7.80 (dd,J = 7.9, 1.5 Hz, 1H), 7.69-7.50 (m, 3H), 5.14 (p, J = 6.6 Hz, 1H), 4.50(q, J = 6.5 Hz, 1H), 4.23 (p, J = 8.3 Hz, 1H), 4.10-3.42 (m, 6H), 3.30(d, J = 11.7 Hz, 2H), 3.07-2.87 (m, 4H), 2.85-2.72 (m, 2H), 2.40 (s,2H), 1.72 (d, J = 28.2 Hz, 9H), 1.53 (d, J = 6.6 Hz, 6H), 1.24 (t, J =6.2 Hz, 3H). 127  735.4 1H NMR (400 MHz, DMSO-d6) delta 10.49 (s, 1H),9.00 (s, 0.07 1H), 8.88 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.38 (d, J =6.5 Hz, 1H), 8.32 (s, 1H), 7.80 (dd, J = 7.8, 1.4 Hz, 1H), 7.66 (dd, J =7.8, 6.4 Hz, 1H), 7.61 (dd, J = 4.7, 3.1 Hz, 2H), 5.13 (p, J = 6.6 Hz,1H), 4.34-4.12 (m, 1H), 3.91 (q, J = 7.5, 5.6 Hz, 4H), 3.48 (s, 3H),3.29 (d, J = 11.5 Hz, 2H), 3.09-2.89 (m, 4H), 2.89- 2.72 (m, 2H), 2.40(s, 2H), 1.72 (d, J = 28.2 Hz, 9H), 1.53 (d, J = 6.6 Hz, 6H), 1.22 (s,5H). 128  693.4 1H NMR (400 MHz, DMSO-d6) delta 10.39 (s, 1H), 8.85 (d,J = 0.07 5.1 Hz, 1H), 8.75 (s, 1H), 8.36 (d, J = 6.4 Hz, 1H), 8.31 (s,1H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.71-7.50 (m, 3H), 5.13 (p, J = 6.6Hz, 1H), 4.31-4.11 (m, 3H), 4.09-3.37 (m, 5H), 3.30 (d, J = 11.8 Hz,2H), 3.10-2.87 (m, 5H), 2.86-2.72 (m, 2H), 2.40 (s, 2H), 1.72 (d, J =28.6 Hz, 9H), 1.53 (d, J = 6.6 Hz, 7H). 129  721.4 1H NMR (400 MHz,Methanol-d4) delta 8.75 (s, 1H), 8.67 (d, 0.6 J = 5.4 Hz, 1H), 8.26 (s,1H), 7.96-7.83 (m, 1H), 7.72 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.54 (d,J = 7.5 Hz, 1H), 5.14 (p, J = 6.8 Hz, 1H), 5.05 (t, J = 6.1 Hz, 2H),4.64-4.49 (m, 1H), 4.44 (t, J = 5.9 Hz, 2H), 4.14 (d, J = 13.7 Hz, 1H),4.05-3.86 (m, 1H), 3.86-3.69 (m, 1H), 3.61 (dd, J = 17.1, 9.7 Hz, 3H),3.24 (dd, J = 19.8, 10.2 Hz, 2H), 3.08-2.80 (m, 5H), 2.56 (s, 3H), 2.04(d, J = 14.6 Hz, 2H), 1.93 (d, J = 6.0 Hz, 6H), 1.82 (s, 1H), 1.75 (s,3H), 1.65 (d, J = 6.6 Hz, 6H). 130  755.3 1H NMR (400 MHz, Chloroform-d)delta 8.86 (s, 1H), 8.28 (d, 1.0 J = 3.0 Hz, 1H), 8.08 (d, J = 2.1 Hz,1H), 7.91-7.82 (m, 2H), 7.72 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 7.8 Hz,1H), 5.29 (p, J = 6.9 Hz, 1H), 5.05 (dd, J = 10.4, 5.9 Hz, 3H), 4.44 (q,J = 6.4, 4.8 Hz, 3H), 4.11 (d, J = 12.8 Hz, 1H), 4.05-3.89 (m, 1H), 3.79(dd, J = 18.0, 10.3 Hz, 3H), 3.43 (dd, J = 19.5, 10.6 Hz, 2H), 3.16 (s,1H), 3.08-2.82 (m, 3H), 2.19-2.01 (m, 1H), 1.93 (d, J = 6.2 Hz, 6H),1.76 (d, J = 2.0 Hz, 3H), 1.73-1.66 (m, 6H), 1.29 (d, J = 22.3 Hz, 6H).131  737.3 1H NMR (400 MHz, Methanol-d4) delta 8.76 (s, 1H), 8.66 (d,0.6 J = 5.5 Hz, 1H), 8.24 (s, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.71(d, J = 1.5 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H),5.13 (p, J = 6.6 Hz, 1H), 4.67-4.45 (m, 1H), 4.23-3.95 (m, 5H),3.89-3.68 (m, 2H), 3.62 (d, J = 8.9 Hz, 2H), 3.57- 3.37 (m, 1H),3.30-3.17 (m, 2H), 2.94 (d, J = 10.7 Hz, 3H), 2.55 (s, 3H), 1.92 (d, J =5.6 Hz, 4H), 1.63 (d, J = 6.7 Hz, 6H), 1.35 (s, 6H), 1.25 (d, J = 12.2Hz, 8H). 132  723.4 1H NMR (400 MHz, Methanol-d4) delta 8.57 (s, 1H),8.21 (d, 0.8 J = 3.6 Hz, 1H), 8.01 (s, 1H), 7.85-7.72 (m, 2H), 7.52 (t,J = 7.6 Hz, 2H), 5.21 (p, J = 6.7 Hz, 1H), 4.37-4.18 (m, 1H), 4.15- 3.95(m, 5H), 3.61 (d, J = 7.7 Hz, 2H), 2.73-2.62 (m, 6H), 2.44 (s, 3H), 1.86(t, J = 5.7 Hz, 4H), 1.64 (d, J = 6.6 Hz, 8H), 1.56- 1.43 (m, 3H), 1.33(d, J = 8.0 Hz, 8H), 1.16 (d, J = 4.0 Hz, 2H). 133  721.3 1H NMR (400MHz, Methanol-d4) delta 8.74 (s, 1H), 8.66 (d, 0.2 J = 5.4 Hz, 1H), 8.25(s, 1H), 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (d, J = 4.8 Hz, 1H),7.65-7.48 (m, 2H), 5.59 (t, J = 8.1 Hz, 1H), 5.14 (p, J = 6.8 Hz, 1H),4.81-4.69 (m, 1H), 4.69-4.53 (m, 2H), 4.34-4.05 (m, 1H), 4.04-3.59 (m,2H), 3.25 (s, 1H), 3.07-2.87 (m, 5H), 2.56 (s, 3H), 2.16-1.77 (m, 8H),1.65 (d, J = 6.7 Hz, 6H), 1.28 (s, 7H). 134  707.4 1H NMR (400 MHz,DMSO-d6) delta 10.39 (s, 1H), 9.47 (s, 0.3 1H), 8.85 (d, J = 5.1 Hz,1H), 8.75 (s, 1H), 8.40-8.27 (m, 2H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H),7.69-7.56 (m, 3H), 5.12 (q, J = 6.6 Hz, 1H), 4.31 (t, J = 8.1 Hz, 1H),3.93 (s, 4H), 3.55-3.32 (m, 5H), 3.05-2.91 (m, 1H), 2.92-2.77 (m, 4H),2.69 (s, 2H), 1.91-1.58 (m, 8H), 1.53 (d, J = 6.6 Hz, 6H), 1.41 (d, J =12.5 Hz, 1H), 0.76 (d, J = 32.3 Hz, 4H). 135  721.5 1H NMR (400 MHz,DMSO-d6) delta 10.55 (s, 1H), 10.34 (s, 0.4 1H), 8.90 (d, J = 5.3 Hz,1H), 8.77 (s, 1H), 8.43-8.28 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H),7.71-7.58 (m, 3H), 5.12 (q, J = 6.7 Hz, 1H), 4.41-4.32 (m, 1H), 3.94 (s,4H), 3.65 (d, J = 28.1 Hz, 2H), 3.34 (d, J = 11.0 Hz, 1H), 2.99 (d, J =10.4 Hz, 2H), 2.81 (d, J = 9.2 Hz, 4H), 1.91 (d, J = 7.0 Hz, 1H), 1.77(dt, J = 11.7, 6.8 Hz, 6H), 1.53 (d, J = 6.6 Hz, 7H), 1.15 (d, J = 24.5Hz, 7H), 0.76 (d, J = 32.5 Hz, 5H). 136  721 1H NMR (400 MHz,Methanol-d4) delta 8.79-8.72 (m, 2H), 0.5 8.32-8.28 (m, 1H), 8.21 (s,1H), 7.86-7.81 (m, 1H), 7.80- 7.73 (m, 1H), 7.67 (s, 1H), 7.52 (d, J =7.9, 1H), 5.19-5.08 (m, 1H), 4.49-4.39 (m, 1H), 4.12-3.74 (m, 6H),3.64-3.48 (m, 3H), 3.25 (s, 3H), 3.22-3.08 (m, 2H), 3.06-2.80 (m, 5H),2.59-2.48 (m, 2H), 2.23-2.09 (m, 2H), 1.99 (d, J = 14.8 Hz, 2H),1.93-1.69 (m, 7H), 1.62 (d, J = 6.5, 6H). 137  735.5 1H NMR (400 MHz,DMSO-d6) delta 9.36 (s, 1H), 8.71 (s, 2H), 0.08 8.33-8.25 (m, 2H), 7.78(d, J = 7.9 Hz, 1H), 7.65 (d, J = 5.1 Hz, 2H), 7.59 (t, J = 6.8 Hz, 1H),5.22-5.07 (m, 1H), 4.78 (dd, J = 20.9, 6.4 Hz, 2H), 4.49 (d, J = 7.4 Hz,2H), 4.30 (t, J = 8.1 Hz, 1H), 3.91-3.77 (m, 4H), 3.39 (d, J = 11.3 Hz,3H), 3.22 (s, 1H), 3.07-2.72 (m, 6H), 2.09 (t, J = 6.7 Hz, 1H),1.96-1.58 (m, 9H), 1.53 (d, J = 6.6 Hz, 6H), 1.41 (d, J = 12.5 Hz, 1H),1.19-0.84 (m, 6H). 138  721.5 1H NMR (400 MHz, DMSO-d6) delta 10.47 (s,1H), 9.51 (s, 0.2 1H), 8.87 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.43-8.30(m, 2H), 7.85-7.74 (m, 1H), 7.69-7.58 (m, 3H), 5.21-5.07 (m, 1H), 4.83(dd, J = 16.0, 6.0 Hz, 2H), 4.34 (ddd, J = 19.3, 12.3, 7.1 Hz, 3H),3.99-3.87 (m, 1H), 3.80 (dt, J = 12.9, 6.2 Hz, 1H), 3.48 (d, J = 8.3 Hz,2H), 3.39 (d, J = 11.8 Hz, 2H), 3.27-3.13 (m, 1H), 3.05-2.88 (m, 2H),2.91-2.73 (m, 5H), 1.98 (q, J = 6.7 Hz, 2H), 1.85 (d, J = 14.0 Hz, 2H),1.75 (q, J = 7.5, 6.5 Hz, 5H), 1.63 (d, J = 13.0 Hz, 1H), 1.53 (d, J =6.6 Hz, 6H), 1.40 (d, J = 12.8 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 139 711.4 1H NMR (400 MHz, DMSO-d6) delta 10.49 (s, 1H), 9.50 (s, 0.5 1H),8.88 (d, J = 5.3 Hz, 1H), 8.76 (s, 1H), 8.41-8.29 (m, 2H), 7.80 (dd, J =7.9, 1.5 Hz, 1H), 7.70-7.59 (m, 3H), 5.22-5.05 (m, 1H), 4.44 (d, J =48.0 Hz, 2H), 4.32 (t, J = 7.9 Hz, 1H), 3.91 (q, J = 4.8, 3.9 Hz, 4H),3.47 (t, J = 7.9 Hz, 1H), 3.40 (d, J = 12.0 Hz, 2H), 2.97 (dt, J = 11.9,9.0 Hz, 2H), 2.91-2.73 (m, 4H), 1.85 (d, J = 14.1 Hz, 3H), 1.81-1.68 (m,5H), 1.63 (d, J = 13.2 Hz, 1H), 1.53 (d, J = 6.6 Hz, 6H), 1.40 (d, J =12.4 Hz, 1H), 1.31 (d, J = 1.7 Hz, 6H). 140  723.5 1H NMR (400 MHz,DMSO-d6) delta 10.36 (s, 1H), 9.45 (s, 0.3 1H), 8.84 (d, J = 5.0 Hz,1H), 8.75 (s, 1H), 8.39-8.29 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H),7.70-7.53 (m, 3H), 5.21-5.06 (m, 1H), 4.30 (d, J = 8.2 Hz, 1H), 3.90 (t,J = 5.7 Hz, 4H), 3.40 (d, J = 15.4 Hz, 4H), 3.29 (s, 3H), 3.02-2.92 (m,2H), 2.90-2.76 (m, 5H), 1.96-1.59 (m, 9H), 1.53 (d, J = 6.6 Hz, 6H),1.41 (d, J = 11.8 Hz, 1H), 1.24 (s, 6H). 141  704.4 1H NMR (400 MHz,DMSO-d6) delta 10.34 (s, 1H), 9.53 (s, 0.3 1H), 8.84 (d, J = 5.1 Hz,1H), 8.74 (s, 1H), 8.41-8.28 (m, 2H), 7.80 (dd, J = 7.9, 1.4 Hz, 1H),7.71-7.59 (m, 3H), 5.14 (p, J = 6.6 Hz, 1H), 4.39-4.26 (m, 1H), 4.00 (s,6H), 3.44 (dd, J = 37.7, 10.0 Hz, 3H), 3.03-2.92 (m, 2H), 2.92-2.73 (m,5H), 1.84 (s, 6H), 1.76-1.32 (m, 13H). 142  702.4 1H NMR (400 MHz,DMSO-d6) delta 10.34 (s, 1H), 9.57 (s, 0.3 1H), 8.84 (d, J = 5.0 Hz,1H), 8.74 (s, 1H), 8.39-8.29 (m, 2H), 7.81 (dd, J = 7.8, 1.5 Hz, 1H),7.70-7.58 (m, 3H), 5.13 (q, J = 6.6 Hz, 1H), 4.38-4.23 (m, 1H), 4.02 (s,4H), 3.45 (dd, J = 37.6, 10.0 Hz, 3H), 3.06-2.74 (m, 6H), 1.85 (d, J =14.4 Hz, 7H), 1.78-1.56 (m, 6H), 1.53 (d, J = 6.6 Hz, 6H), 1.48-1.33 (m,1H). 143  677.4 1H NMR (400 MHz, DMSO-d6) delta 10.36 (s, 1H), 9.52 (s,0.3 1H), 8.84 (d, J = 5.1 Hz, 1H), 8.74 (d, J = 1.3 Hz, 1H), 8.36 (dd, J= 6.5, 2.2 Hz, 1H), 8.32 (s, 1H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H),7.68-7.59 (m, 3H), 5.21-5.09 (m, 1H), 4.37-4.25 (m, 1H), 4.04 (s, 3H),3.89 (s, 1H), 3.80 (d, J = 6.9 Hz, 0H), 3.44 (dd, J = 33.8, 9.9 Hz, 3H),3.07-2.77 (m, 5H), 2.04 (td, J = 7.5, 3.9 Hz, 1H), 1.90-1.59 (m, 9H),1.53 (d, J = 6.6 Hz, 6H), 1.48-1.33 (m, 0H), 1.30-1.22 (m, 1H),1.00-0.90 (m, 1H), 0.77 (ddd, J = 20.5, 7.5, 3.9 Hz, 4H). 144  693.4 1HNMR (500 MHz, DMSO-d6) delta 9.05 (d, J = 2.2 Hz, 1H), 0.3 8.61 (s, 1H),8.42 (d, J = 3.4 Hz, 1H), 8.18 (t, J = 2.7 Hz, 2H), 8.03 (s, 1H), 7.74(dd, J = 7.9, 1.5 Hz, 1H), 7.58-7.51 (m, 2H), 5.23-5.14 (m, 1H),4.78-4.69 (m, 4H), 4.49 (t, J = 8.5 Hz, 1H), 4.18 (t, J = 7.8 Hz, 1H),3.98-3.90 (m, 1H), 3.80-3.71 (m, 1H), 3.62 (td, J = 8.6, 8.0, 4.3 Hz,1H), 3.36 (d, J = 13.9 Hz, 1H), 2.58 (t, J = 9.2 Hz, 1H), 2.50 (p, J =1.9 Hz, 2H), 2.26 (s, 4H), 1.70 (d, J = 5.5 Hz, 6H), 1.61-1.56 (m, 4H),1.53 (d, J = 6.6 Hz, 6H), 1.43 (s, 2H). 145  709.5 1H NMR (400 MHz,DMSO-d6) delta 9.40 (s, 1H), 8.80 (s, 1H), 0.4 8.73 (s, 1H), 8.38-8.27(m, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.70- 7.56 (m, 3H), 5.13 (t, J = 6.6Hz, 1H), 4.40-4.14 (m, 4H), 3.89 (s, 2H), 3.43 (dd, J = 35.5, 9.7 Hz,3H), 3.21 (s, 3H), 2.96 (s, 2H), 2.82 (s, 4H), 1.94-1.56 (m, 8H), 1.52(d, J = 6.6 Hz, 6H), 1.38 (s, 7H) 146  707.5 1H NMR (400 MHz, DMSO-d6)delta 9.40 (s, 1H), 8.79 (s, 1H), 0.3 8.73 (s, 1H), 8.37-8.27 (m, 2H),7.79 (d, J = 7.9 Hz, 1H), 7.68- 7.57 (m, 3H), 5.21-5.03 (m, 1H),4.40-4.19 (m, 1H), 4.06 (s, 7H), 3.57-3.34 (m, 2H), 3.29 (s, 3H), 2.96(d, J = 10.1 Hz, 2H), 2.83 (s, 4H), 1.92-1.56 (m, 7H), 1.52 (d, J = 6.6Hz, 7H), 0.97 (d, J = 41.3 Hz, 4H). 147  707.5 1H NMR (400 MHz, DMSO-d6)delta 9.41 (s, 1H), 8.81 (s, 1H), 0.4 8.73 (s, 1H), 8.38-8.28 (m, 2H),7.78 (d, J = 7.9 Hz, 1H), 7.70- 7.54 (m, 3H), 5.21-5.05 (m, 1H), 4.86(dd, J = 18.8, 5.8 Hz, 2H), 4.30 (t, J = 6.8 Hz, 3H), 3.92 (s, 1H), 3.76(s, 1H), 3.57- 3.41 (m, 3H), 3.38 (d, J = 11.8 Hz, 2H), 3.18 (d, J =11.3 Hz, 1H), 2.95 (dd, J = 29.9, 10.0 Hz, 2H), 2.82 (s, 4H), 1.78 (d, J= 35.2 Hz, 8H), 1.64-1.32 (m, 9H). 148  665.4 1H NMR (400 MHz, DMSO-d6)delta 10.46 (s, 1H), 9.55 (s, 1.3 1H), 8.88 (d, J = 5.2 Hz, 1H), 8.58(s, 1H), 8.37 (d, J = 6.5 Hz, 1H), 8.31 (s, 1H), 7.78 (dd, J = 7.8, 1.4Hz, 1H), 7.72 (dd, J = 7.7, 6.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.60(d, J = 7.9 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 4.29 (t, J = 8.2 Hz, 1H),3.97- 3.70 (m, 4H), 3.42 (dd, J = 34.8, 9.9 Hz, 4H), 3.02-2.70 (m, 5H),1.90-1.51 (m, 9H), 1.33 (t, J = 7.2 Hz, 3H), 1.03 (dd, J = 9.3, 6.6 Hz,6H). 149  709.4 1H NMR (400 MHz, DMSO-d6) delta 10.36 (s, 1H), 9.45 (s,0.5 1H), 8.84 (d, J = 5.0 Hz, 1H), 8.75 (s, 1H), 8.39-8.30 (m, 2H), 7.79(d, J = 7.8 Hz, 1H), 7.69-7.57 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H), 4.31(t, J = 8.2 Hz, 1H), 4.01-3.90 (m, 1H), 3.90-3.78 (m, 2H), 3.71 (d, J =12.9 Hz, 1H), 3.54-3.44 (m, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.06-2.63(m, 9H), 2.42 (d, J = 18.5 Hz, 3H), 1.97-1.57 (m, 9H), 1.52 (d, J = 6.6Hz, 6H), 1.42 (t, J = 12.7 Hz, 1H). 150  695.5 1H NMR (400 MHz, DMSO-d6)delta 10.42 (s, 1H), 9.51 (s, 0.5 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.75(s, 1H), 8.40-8.28 (m, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.70-7.56 (m, 3H),5.13 (p, J = 6.6 Hz, 1H), 4.38-4.24 (m, 1H), 3.99 (s, 3H), 3.44 (dd, J =32.7, 10.1 Hz, 3H), 2.97 (d, J = 10.1 Hz, 2H), 2.85 (d, J = 9.7 Hz, 5H),1.74 (d, J = 74.3 Hz, 8H), 1.53 (d, J = 6.6 Hz, 6H), 1.47-1.18 (m, 5H).151  707.5 1H NMR (400 MHz, DMSO-d6) delta 10.59 (s, 1H), 9.72 (s, 0.31H), 8.93 (d, J = 5.3 Hz, 1H), 8.61 (s, 1H), 8.42 (d, J = 6.6 Hz, 1H),8.34 (s, 1H), 7.86-7.71 (m, 2H), 7.70-7.59 (m, 2H), 4.55 (q, J = 7.2 Hz,2H), 4.31 (t, J = 8.1 Hz, 1H), 3.98-3.71 (m, 4H), 3.45 (dd, J = 38.4,9.6 Hz, 3H), 3.05-2.70 (m, 6H), 2.45 (d, J = 2.5 Hz, 6H), 1.91-1.60 (m,10H), 1.36 (t, J = 7.2 Hz, 3H), 0.99- 0.88 (m, 1H). 152  695.4 1H NMR(400 MHz, DMSO-d6) delta 10.28 (s, 1H), 9.49 (s, 0.5 1H), 8.82 (d, J =4.9 Hz, 1H), 8.74 (s, 1H), 8.39-8.28 (m, 2H), 7.79 (d, J = 7.6 Hz, 1H),7.71-7.54 (m, 3H), 5.14 (p, J = 6.4 Hz, 1H), 4.29 (p, J = 7.1, 6.5 Hz,2H), 3.89 (d, J = 29.8 Hz, 4H), 3.44 (dd, J = 34.8, 9.8 Hz, 4H), 3.26(s, 3H), 3.05-2.76 (m, 7H), 1.92-1.56 (m, 8H), 1.53 (d, J = 6.6 Hz, 6H),1.49-1.33 (m, 1H), 1.28 (dd, J = 6.8, 2.0 Hz, 3H). 153  695.5 1H NMR(400 MHz, DMSO-d6) delta 10.52 (s, 1H), 9.52 (s, 0.3 1H), 8.89 (d, J =5.2 Hz, 1H), 8.77 (s, 1H), 8.41-8.31 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H),7.70-7.54 (m, 3H), 5.12 (q, J = 6.6 Hz, 1H), 4.31 (dd, J = 16.2, 7.9 Hz,2H), 3.89 (d, J = 29.2 Hz, 5H), 3.44 (dd, J = 32.7, 10.0 Hz, 3H), 3.26(s, 3H), 2.96 (dd, J = 21.7, 10.3 Hz, 1H), 2.84 (d, J = 10.3 Hz, 5H),1.74 (ddd, J = 49.3, 34.8, 13.7 Hz, 9H), 1.52 (d, J = 6.6 Hz, 7H), 1.40(d, J = 12.6 Hz, 0H), 1.28 (dd, J = 6.6, 2.0 Hz, 3H). 154  718 1H NMR(400 MHz, Methanol-d4) delta 8.93 (s, 1H), 8.79 (d, 0.3 J = 5.6 Hz, 1H),8.41 (s, 1H), 8.34 (d, J = 6.9 Hz, 1H), 8.31-8.20 (m, 2H), 7.87-7.79 (m,2H), 7.69 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.19 (p, J = 6.7 Hz, 1H),4.57-3.68 (m, 7H), 3.34 (s, 2H), 3.26-3.14 (m, 2H), 3.00-2.86 (m, 2H),2.10-1.85 (m, 6H), 1.63 (d, J = 6.7 Hz, 6H), 1.24 (s, 6H). 155  718 1HNMR (400 MHz, Methanol-d4) delta 8.84-8.81 (m, 1H), 0.3 8.57 (s, 1H),8.37 (d, J = 3.7 Hz, 1H), 8.19-8.11 (m, 1H), 8.00 (s, 1H), 7.79 (dd, J =7.9, 1.6 Hz, 1H), 7.72 (s, 1H), 7.69-7.64 (m, 1H), 7.58-7.50 (m, 1H),6.79-6.76 (m, 1H), 5.26-5.14 (m, 1H), 4.43-4.26 (m, 2H), 4.22-4.02 (m,4H), 3.60-3.45 (m, 2H), 3.08-2.73 (m, 6H), 2.07-1.84 (m, 6H), 1.63 (d, J= 6.7, 6H), 1.20 (s, 6H). 156  734 1H NMR (400 MHz, Methanol-d4) delta8.57 (s, 1H), 8.37 (d, 0.2 J = 3.6 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H),7.99 (s, 1H), 7.78 (dd, J = 7.9, 1.5 Hz, 1H), 7.73-7.64 (m, 2H), 7.52(d, J = 7.9 Hz, 1H), 5.25-5.17 (m, 1H), 4.42-4.31 (m, 1H), 4.09-3.74 (m,5H), 3.60-3.40 (m, 2H), 3.25 (s, 3H), 3.17-2.73 (m, 8H), 2.59- 2.47 (m,2H), 2.26-2.08 (m, 2H), 1.97-1.74 (m, 6H), 1.63 (d, J = 6.7 Hz, 6H),1.20 (s, 6H). 157  715 1H NMR (400 MHz, Methanol-d4) delta 8.57 (s, 1H),8.38 (s, 0.3 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J =7.9, 1H), 7.72-7.60 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 5.27-5.16 (m,1H), 4.42-4.34 (m, 1H), 4.10-3.95 (m, 4H), 3.76-3.59 (m, 2H), 3.48-3.35(m, 3H), 3.25 (s, 3H), 3.15-2.95 (, 4H), 2.92- 2.76 (m, 2H), 2.65-2.46(m, 2H), 2.34-2.18 (m, 2H), 2.05- 1.74 (m, 6H), 1.63 (d, J = 6.6 Hz,6H), 1.22 (s, 6H). 158  718 1H NMR (400 MHz, Methanol-d4) delta 8.55 (s,1H), 8.38- 0.4 8.33 (m, 2H), 8.15 (d, J = 5.3 Hz, 1H), 7.97 (s, 1H),7.87-7.64 (m, 4H), 7.51 (d, J = 7.8 Hz, 1H), 5.28-5.16 (m, 1H), 4.36-3.95 (m, 5H), 2.98-2.86 (m, 1H), 2.81-2.53 (m, 6H), 2.41 (s, 2H),2.07-1.75 (m, 4H), 1.63 (d, J = 6.6 Hz, 6H), 1.35-1.25 (m, 2H),1.18-0.99 (s, 6H). 159  718 1H NMR (400 MHz, Methanol-d4) delta 8.55 (d,J = 2.0 Hz, 0.4 1H), 8.34 (d, J = 3.4 Hz, 1H), 8.15 (d, J = 5.4 Hz, 1H),8.07 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.84-7.64 (m, 3H),7.48 (dd, J = 7.7, 2.2 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 5.30-5.11 (m,1H), 4.55-3.99 (m, 6H), 3.03-2.92 (m, 1H), 2.85-2.54 (m, 6H), 2.47 (s,2H), 2.07-1.83 (m, 4H), 1.74-1.55 (m, 7H), 1.09 (d, J = 2.2 Hz, 6H).160  719 1H NMR (400 MHz, Methanol-d4) delta 9.47(s, 1H), 8.79-8.68 0.4(m, 2H), 8.29 (dd, J = 6.8, 1.1 Hz, 1H), 8.20 (s, 1H), 7.85 (dd, J =7.8, 1.7 Hz, 1H), 7.79-7.66 (m, 2H), 7.59-7.52 (m, 1H), 5.18-5.10 (m,1H), 4.58-4.48 (m, 1H), 4.42-4.03 (m, 5H), 4.00- 3.70 (m, 4H), 3.28-3.14(m, 2H), 3.00-2.84 (m, 2H), 2.13- 1.87 (m, 6H), 1.62 (d, J = 6.6, 6H),1.25 (s, 6H). 161  732 1H NMR (400 MHz, Methanol-d4) delta 8.79-8.70 (m,2H), 0.4 8.29 (d, J = 6.9 Hz, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.86 (dd,J = 7.9, 1.8 Hz, 1H), 7.78-7.68 (m, 2H), 7.61-7.55 (m, 1H), 5.20- 5.09(m, 1H), 4.58-4.47 (m, 1H), 4.38-4.24 (m, 1H), 4.21 (s, 3H), 4.16-4.35(m, 8H), 3.26-3.15 (m, 2H), 2.98-2.86 (m, 2H), 2.10-1.86 (m, 6H), 1.62(d, J = 6.6 Hz, 6H), 1.25 (s, 6H). 162  734 1H NMR (400 MHz,Methanol-d4) delta 8.76 (s, 2H), 8.39-815 0.1 (m, 2H), 7.96 (d, J = 2.9Hz, 1H), 7.89-7.64 (m, 4H), 7.55 (d, J = 7.6 Hz, 1H), 5.18-5.10 (m, 1H),4.96-4.88 (m, 1H), 4.65- 4.45 (m, 2H), 4.35-4.25 (m, 1H), 4.15-4.05 (m,1H), 3.90 3.35 (m, 4H), 3.28-3.14 (m, 2H), 3.02-3.86 (m, 2H), 2.15- 1.85(m, 6H), 1.62 (d, J = 6.4 Hz, 6H), 1.24 (s, 6H). 163  715 1H NMR (400MHz, Methanol-d4) delta 8.83-8.70 (m, 2H), 0.3 8.33-8.29 (m, 1H), 8.23(s, 1H), 7.91-7.85 (m, 1H), 7.79- 7.73 (m, 1H), 7.70 (s, 1H), 7.59 (d, J= 7.9 Hz, 1H), 5.21-5.11 (m, 1H), 5.04 (t, J = 5.9 Hz, 2H), 4.56-4.48(m, 1H), 4.43 (t, J = 5.9 Hz, 2H), 4.21-3.65 (m, 6H), 3.21-2.76 (m, 6H),2.18-1.46 (m, 18H). 164  741.5 1H NMR (400 MHz, DMSO-d6) delta 10.23 (d,J = 8.8 Hz, 1H), 0.08 8.71 (s, 1H), 8.61 (s, 1H), 8.19 (dt, J = 9.5, 7.8Hz, 1H), 7.89 (s, 1H), 7.64-7.52 (m, 2H), 7.43 (d, J = 1.4 Hz, 1H), 7.25(dd, J = 8.3, 2.8 Hz, 1H), 5.28 (p, J = 6.6 Hz, 1H), 4.22 (t, J = 8.2Hz, 1H), 4.00 (d, J = 4.7 Hz, 0H), 3.90 (t, J = 5.8 Hz, 4H), 3.77- 3.57(m, 2H), 3.47 (s, 2H), 3.42-3.32 (m, 1H), 3.33-3.20 (m, 1H), 2.98 (dq, J= 26.1, 9.8 Hz, 2H), 2.89-2.73 (m, 3H), 1.94 (ddd, J = 13.0, 8.5, 6.3Hz, 1H), 1.75 (dt, J = 21.8, 7.2 Hz, 5H), 1.61 (d, J = 6.5 Hz, 6H), 1.21(s, 6H), 1.16 (d, J = 27.3 Hz, 7H). 165  739.4 1H NMR (400 MHz, DMSO-d6)delta 10.28 (d, J = 9.7 Hz, 1H), 0.06 8.74 (s, 1H), 8.63 (s, 1H),8.25-8.13 (m, 1H), 7.89 (s, 1H), 7.60 (s, 2H), 7.43 (s, 1H), 7.25 (dd, J= 8.3, 2.8 Hz, 1H), 5.28 (q, J = 6.6 Hz, 1H), 4.86 (dd, J = 21.3, 5.9Hz, 2H), 4.30 (t, J = 5.6 Hz, 2H), 4.21 (t, J = 8.3 Hz, 1H), 3.96-3.84(m, 1H), 3.84-3.54 (m, 3H), 3.47 (d, J = 5.0 Hz, 1H), 3.36 (dd, J =11.4, 5.4 Hz, 1H), 3.23 (ddd, J = 28.3, 13.1, 7.3 Hz, 1H), 2.96 (dt, J =24.4, 11.7 Hz, 1H), 2.81 (ddd, J = 15.8, 9.6, 5.8 Hz, 3H), 1.93 (ddd, J= 14.2, 8.4, 6.2 Hz, 1H), 1.85-1.69 (m, 5H), 1.66-1.52 (m, 10H), 1.15(d, J = 27.5 Hz, 7H). 166  691.4 1H NMR (400 MHz, Methanol-d4) delta8.78 (s, 1H), 8.65 (d, 0.1 J = 5.5 Hz, 1H), 8.24 (s, 1H), 7.88 (dd, J =7.9, 1.5 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 7.54 (dd, J = 11.1, 7.6 Hz,2H), 5.13 (p, J = 6.7 Hz, 1H), 4.63 (p, J = 7.8 Hz, 1H), 4.20 (dt, J =13.4, 4.8 Hz, 1H), 4.05 (ddd, J = 13.5, 9.3, 4.1 Hz, 1H), 3.87 (ddd, J =20.6, 13.4, 5.9 Hz, 2H), 3.68 (p, J = 7.3 Hz, 1H), 3.56-3.45 (m, 2H),3.26-3.07 (m, 2H), 3.01 (dd, J = 13.3, 9.7 Hz, 4H), 2.54 (s, 4H), 2.21(s, 3H), 2.08-1.95 (m, 4H), 1.91 (d, J = 7.1 Hz, 4H), 1.79 (d, J = 12.0Hz, 1H), 1.62 (d, J = 6.7 Hz, 6H), 1.38-1.26 (m, 1H). 167  665.5 1H NMR(400 MHz, DMSO-d6) delta 10.54 (s, 1H), 9.52 (s, 0.4 1H), 8.90 (d, J =5.2 Hz, 1H), 8.77 (s, 1H), 8.42-8.31 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H),7.69-7.55 (m, 3H), 5.12 (q, J = 6.7 Hz, 1H), 4.31 (p, J = 8.3 Hz, 1H),3.97-3.67 (m, 3H), 3.44 (dd, J = 31.4, 10.0 Hz, 3H), 2.90 (dt, J = 60.4,13.5 Hz, 7H), 2.41 (qd, J = 7.7, 2.4 Hz, 2H), 1.92-1.58 (m, 8H), 1.52(d, J = 6.6 Hz, 7H), 1.42 (t, J = 12.6 Hz, 1H), 1.04 (t, J = 7.4 Hz,3H). 168  651.4 1H NMR (400 MHz, DMSO-d6) delta 9.04 (d, J = 2.3 Hz,1H), 2.6 8.45 (d, J = 5.9 Hz, 2H), 8.20 (d, J = 5.4 Hz, 1H), 8.16 (s,1H), 8.05 (s, 1H), 7.76 (dd, J = 7.9, 1.5 Hz, 1H), 7.68 (dd, J = 7.3,5.4 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 4.57 (q, J = 7.2 Hz, 3H), 3.95-3.64 (m, 6H), 2.60 (s, 2H), 2.45-2.33 (m, 2H), 2.26 (s, 3H), 1.81-1.52(m, 10H), 1.43 (s, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.4 Hz,3H). 169  679.5 1H NMR (400 MHz, DMSO-d6) delta 10.56 (s, 1H), 9.66 (s,0.8 1H), 8.92 (d, J = 5.3 Hz, 1H), 8.61 (s, 1H), 8.41 (d, J = 6.5 Hz,1H), 8.34 (s, 1H), 7.85-7.71 (m, 2H), 7.70-7.60 (m, 2H), 4.55 (q, J =7.2 Hz, 2H), 4.32 (t, J = 7.9 Hz, 1H), 3.92 (t, J = 5.8 Hz, 4H), 3.45(dd, J = 36.9, 9.9 Hz, 3H), 2.97 (dt, J = 11.3, 8.6 Hz, 3H), 2.92-2.72(m, 4H), 1.92-1.55 (m, 9H), 1.35 (t, J = 7.2 Hz, 4H), 1.26 (s, 9H). 170 693.4 1H NMR (400 MHz, DMSO-d6) delta 10.52 (s, 1H), 9.55 (s, 0.3 1H),8.89 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.42-8.30 (m, 2H), 7.80 (dd, J =7.8, 1.5 Hz, 1H), 7.69-7.56 (m, 3H), 5.12 (q, J = 6.7 Hz, 1H), 4.30 (q,J = 8.3 Hz, 1H), 3.91 (t, J = 5.7 Hz, 4H), 3.44 (dd, J = 34.2, 10.0 Hz,3H), 3.04-2.89 (m, 2H), 2.90-2.75 (m, 5H), 1.85 (d, J = 14.0 Hz, 2H),1.80-1.56 (m, 6H), 1.53 (d, J = 6.6 Hz, 6H), 1.40 (q, J = 12.7, 11.9 Hz,1H), 1.26 (s, 9H). 171  679.5 1H NMR (400 MHz, DMSO-d6) delta 10.49 (s,1H), 9.48 (s, 0.5 1H), 8.88 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.40-8.31(m, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.70-7.56 (m, 3H), 5.19-5.07 (m, 1H),4.33 (q, J = 8.2 Hz, 1H), 3.98-3.73 (m, 4H), 3.44 (dd, J = 31.5, 9.9 Hz,3H), 2.96 (td, J = 14.3, 13.1, 7.7 Hz, 2H), 2.83 (t, J = 12.2 Hz, 5H),1.91-1.56 (m, 9H), 1.52 (d, J = 6.6 Hz, 6H), 1.42 (t, J = 13.1 Hz, 1H),1.05 (dd, J = 9.1, 6.5 Hz, 6H). 172  663.3 1H NMR (400 MHz, DMSO-d6)delta 10.42-10.20 (s, 2H), 0.1 8.84-8.79 (m, 1H), 8.74 (s, 1H),8.40-8.25 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.64-7.57 (t,J = 8.3 Hz, 2H), 5.14 (p, J = 6.5 Hz, 1H), 4.34 (p, J = 8.2 Hz, 1H),3.95-3.82 (m, 2H), 3.81-3.54 (m, 5H), 3.20-3.12 (m, 3H), 3.11-3.01 (m,3H), 2.82 (d, J = 8.9 Hz, 2H), 2.27-2.17 (m, 2H), 2.09 (s, 3H), 1.87-1.78 (m, 4H), 1.74-1.69 (m, 2H), 1.53 (d, J = 6.5 Hz, 6H). 173  679.4 1HNMR (400 MHz, Methanol-d4) delta 8.77 (s, 1H), 8.66 (d, 0.4 J = 5.5 Hz,1H), 8.24 (s, 1H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 (d, J = 1.5 Hz,1H), 7.54 (dd, J = 11.1, 7.7 Hz, 2H), 5.13 (p, J = 6.7 Hz, 1H), 4.57 (p,J = 8.4 Hz, 1H), 4.23-3.97 (m, 2H), 3.98- 3.67 (m, 4H), 3.56-3.39 (m,2H), 3.24 (t, J = 10.8 Hz, 2H), 2.94 (d, J = 12.1 Hz, 4H), 2.54 (s, 3H),2.21 (s, 3H), 2.06-1.92 (m, 4H), 1.87 (t, J = 5.8 Hz, 2H), 1.69-1.57 (m,6H), 1.26 (s, 6H). 174  665.4 1H NMR (400 MHz, DMSO-d6) delta 10.48 (s,1H), 9.90 (s, 0.5 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.75 (s, 1H), 8.42-8.27(m, 2H), 7.83 (d, J = 7.7 Hz, 1H), 7.72-7.55 (m, 2H), 7.38-7.17 (m, 1H),5.13 (p, J = 6.6 Hz, 1H), 4.79 (dt, J = 25.9, 7.3 Hz, 4H), 4.34-4.11 (m,1H), 3.70-3.08 (m, 7H), 3.08-2.67 (m, 6H), 2.31 (s, 1H), 2.01 (d, J =34.6 Hz, 1H), 1.83 (d, J = 14.0 Hz, 2H), 1.66 (dd, J = 36.8, 13.3 Hz,2H), 1.51 (d, J = 6.6 Hz, 6H), 1.38 (d, J = 12.7 Hz, 1H). 175  651.3 1HNMR (400 MHz, DMSO-d6) delta 10.46 (s, 1H), 9.88 (d, J = 0.8 34.1 Hz,1H), 8.88 (d, J = 5.1 Hz, 1H), 8.59 (s, 1H), 8.39 (d, J = 6.4 Hz, 1H),8.33 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.75 (t, J = 7.1 Hz, 1H), 7.65(s, 1H), 4.79 (dt, J = 26.3, 7.4 Hz, 4H), 4.54 (q, J = 7.2 Hz, 2H), 4.28(q, J = 8.3 Hz, 1H), 3.41 (dd, J = 42.2, 13.6 Hz, 8H), 3.03-2.70 (m,7H), 2.44-1.91 (m, 3H), 1.83 (d, J = 13.9 Hz, 2H), 1.66 (dd, J = 37.4,13.8 Hz, 3H), 1.33 (t, J = 7.2 Hz, 4H). 176  665 1H NMR (400 MHz,Methanol-d4) delta 8.79-8.70 (m, 2H), 0.8 8.29 (d, J = 6.7 Hz, 1H), 8.21(s, 1H), 7.90-7.85 (m, 1H), 7.76- 7.68 (m, 2H), 7.49-7.36 (m, 1H),5.18-5.08 (m, 1H), 5.00- 4.86 (m, 4H), 4.62-4.48 (m, 2H), 3.96 (s, 4H),3.91-3.69 (m, 3H), 3.57-3.45 (m, 2H), 3.20-3.09 (m, 2H), 2.86-2.76 (m,2H), 2.44-2.10 (m, 4H), 1.62 (d, J = 6.7 Hz, 6H), 1.39 (s, 6H). 177 677.4 1H NMR (400 MHz, DMSO-d6) delta 10.65 (s, 1H), 9.62 (d, J = 0.310.5 Hz, 1H), 8.91 (d, J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.38 (d, J = 6.6Hz, 1H), 8.33 (s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 (dd, J =7.7, 6.6 Hz, 1H), 7.62-7.54 (m, 2H), 5.11 (p, J = 6.6 Hz, 1H), 4.25 (p,J = 8.3 Hz, 1H), 3.86 (td, J = 16.0, 14.7, 7.5 Hz, 1H), 3.72 (p, J = 7.0Hz, 2H), 3.57-3.31 (m, 2H), 3.15 (t, J = 10.6 Hz, 1H), 3.10-2.66 (m,6H), 2.06 (s, 3H), 1.94-1.73 (m, 6H), 1.73-1.61 (m, 2H), 1.50 (t, J =4.3 Hz, 6H), 1.01 (d, J = 9.7 Hz, 1H), 0.72-0.30 (m, 4H). 178  663.4 1HNMR (400 MHz, DMSO-d6) delta 10.64 (s, 1H), 10.53 (s, 0.8 1H), 8.91 (d,J = 5.4 Hz, 1H), 8.76 (s, 1H), 8.44-8.30 (m, 2H), 7.77 (dd, J = 7.8, 1.4Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.62 (dd, J = 7.8, 6.6 Hz, 1H), 7.57(d, J = 7.8 Hz, 1H), 5.10 (p, J = 6.7 Hz, 1H), 4.37 (p, J = 8.4 Hz, 1H),3.99-3.78 (m, 1H), 3.70 (dd, J = 13.8, 6.5 Hz, 4H), 3.41-3.18 (m, 2H),3.12 (t, J = 8.5 Hz, 1H), 2.98 (dd, J = 19.3, 9.7 Hz, 2H), 2.81 (d, J =10.4 Hz, 2H), 2.07 (s, 3H), 1.95-1.62 (m, 4H), 1.50 (dd, J = 6.6, 1.5Hz, 6H), 0.72 (d, J = 6.6 Hz, 3H), 0.62 (d, J = 5.5 Hz, 1H). 179  683.41H NMR (400 MHz, DMSO-d6) delta 10.64 (s, 1H), 9.04 (s, 4.5 1H), 8.91(d, J = 5.3 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 6.6 Hz, 1H), 8.33 (s,1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H), 7.64 (d, J = 3.4 Hz, 1H), 7.60 (dd,J = 14.2, 7.9 Hz, 2H), 5.11 (p, J = 6.6 Hz, 1H), 4.26 (p, J = 8.3 Hz,1H), 3.85 (td, J = 12.9, 12.0, 7.3 Hz, 1H), 3.78-3.54 (m, 3H), 3.17 (s,5H), 2.88 (d, J = 14.0 Hz, 3H), 2.81 (s, 4H), 2.07 (s, 3H), 1.86-1.74(m, 2H), 1.74-1.60 (m, 2H), 1.57-1.39 (m, 6H), 1.24 (s, 6H). 180  649.31H NMR (400 MHz, DMSO-d6) delta 10.60 (s, 1H), 9.91 (s, 1.3 1H), 8.90(d, J = 5.3 Hz, 1H), 8.75 (s, 1H), 8.38 (d, J = 6.6 Hz, 1H), 8.34 (s,1H), 7.83-7.74 (m, 1H), 7.68-7.61 (m, 2H), 7.56 (d, J = 7.9 Hz, 1H),5.11 (p, J = 6.6 Hz, 1H), 4.30 (p, J = 8.3 Hz, 1H), 3.97-3.76 (m, 1H),3.76-3.50 (m, 4H), 3.27 (d, J = 11.1 Hz, 2H), 3.09-2.78 (m, 2H), 2.75(d, J = 9.0 Hz, 2H), 2.06 (s, 3H), 1.90-1.73 (m, 5H), 1.67 (t, J = 6.0Hz, 2H), 1.50 (d, J = 6.6 Hz, 6H), 0.79-0.56 (m, 2H). 181  677.4 1H NMR(400 MHz, DMSO-d6) delta 10.21 (s, 1H), 8.83 (d, J = 0.1 24.0 Hz, 2H),8.73 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.29 (s, 1H), 7.79(d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.3 Hz, 3H), 5.28-4.99 (m, 1H), 4.23(t, J = 8.2 Hz, 1H), 3.88 (q, J = 11.4, 8.0 Hz, 2H), 3.74 (dd, J = 11.9,6.1 Hz, 2H), 3.54 (d, J = 9.3 Hz, 1H), 3.29 (d, J = 11.5 Hz, 2H), 2.96(dt, J = 20.3, 10.3 Hz, 4H), 2.79 (s, 2H), 2.40 (s, 2H), 2.09 (d, J =2.0 Hz, 3H), 1.74 (q, J = 14.0, 9.3 Hz, 9H), 1.53 (d, J = 6.6 Hz, 7H).182  691.4 1H NMR (400 MHz, DMSO-d6) delta 10.39 (s, 1H), 9.20 (s, 0.31H), 8.85 (d, J = 5.1 Hz, 1H), 8.75 (s, 1H), 8.41-8.26 (m, 2H), 7.79(dd, J = 7.8, 1.5 Hz, 1H), 7.67-7.52 (m, 3H), 5.13 (p, J = 6.6 Hz, 1H),4.27 (q, J = 8.2 Hz, 1H), 3.91-3.82 (m, 4H), 3.79- 3.69 (m, 2H), 3.44(m, 2H), 3.32 (d, J = 11.9 Hz, 1H), 3.11- 2.78 (m, 3H), 2.70 (m, 2H),2.09 (s, 3H), 1.96-1.57 (m, 6H), 1.53 (d, J = 6.5 Hz, 6H), 1.42 (t, J =12.9 Hz, 1H). 183  663.4 1H NMR (400 MHz, DMSO-d6) delta 10.31 (s, 1H),9.34 (s, 0.4 1H), 8.82 (d, J = 4.9 Hz, 1H), 8.74 (s, 1H), 8.35 (d, J =6.3 Hz, 1H), 8.31 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.68-7.50 (m, 3H),5.13 (p, J = 6.7 Hz, 1H), 4.29 (p, J = 8.4 Hz, 1H), 3.95-3.79 (m, 3H),3.75 (q, J = 6.5 Hz, 1H), 3.34 (s, 1H), 3.15 (s, 1H), 2.84 (s, 5H), 2.21(d, J = 13.9 Hz, 1H), 2.09 (s, 3H), 1.99 (d, J = 14.3 Hz, 1H), 1.82 (dd,J = 15.4, 7.4 Hz, 2H), 1.70 (t, J = 5.9 Hz, 2H), 1.53 (d, J = 6.5 Hz,6H), 1.19 (s, 2H), 0.81 (td, J = 8.8, 5.0 Hz, 1H), 0.54 (d, J = 5.6 Hz,1H). 184  665.4 1H NMR (400 MHz, DMSO-d6, ~1:1 mixture of diastereomeric0.7 protonation states) delta 10.59 (s, 1H), 9.67 (t, J = 7.2 Hz, 0.5H),9.44-9.35 (m, 0.5H), 8.90 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.38 (d, J= 6.6 Hz, 1H), 8.34 (d, J = 5.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H),7.67-7.56 (m, 3H), 5.12 (p, J = 6.6 Hz, 1H), 4.27 (dp, J = 23.7, 7.7,7.2 Hz, 1H), 3.96-3.81 (m, 2H), 3.78-3.62 (m, 3H), 3.55 (td, J = 16.5,8.4 Hz, 0.5H), 3.44 (d, J = 12.2 Hz, 0.5H), 3.31-3.11 (m, 1.5H),3.07-2.77 (m, 4.5H), 2.08 (s, 3H), 1.89- 1.44 (m, 17H), 1.29 (d, J = 5.2Hz, 1.5H), 1.25 (d, J = 6.8 Hz, 1.5H). 185  665.4 1H NMR (400 MHz,DMSO-d6) delta 10.58(s, 1H), 9.76 (s, 0.1 1H), 8.91 (d, J = 5.3 Hz, 1H),8.77 (s, 1H), 8.44-8.22 (m, 2H), 7.80 (dd, J = 7.8, 1.5 Hz, 1H),7.76-7.51 (m, 3H), 5.14 (p, J = 6.7 Hz, 1H), 4.25 (p, J = 8.2 Hz, 1H),3.88 (ddt, J = 22.3, 12.8, 4.6 Hz, 2H), 3.73 (p, J = 6.3 Hz, 2H), 3.63(hept, J = 8.4 Hz, 1H), 3.42-3.28 (m, 2H), 3.13-2.82 (m, 6H), 2.09 (s,3H), 1.92-1.58 (m, 14H), 1.53 (d, J = 6.5 Hz, 6H). 186  677.4 1H NMR(400 MHz, DMSO-d6) delta 10.46 (d, J = 44.0 Hz, 0.3 1H), 9.50 (dd, J =69.9, 9.9 Hz, 1H), 8.85 (d, J = 5.2 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H),8.43-8.24 (m, 2H), 7.84-7.74 (m, 1H), 7.66-7.53 (m, 3H), 5.13 (p, J =6.7 Hz, 1H), 4.16 (p, J = 8.2 Hz, 1H), 3.89 (q, J = 10.2, 6.1 Hz, 5H),3.80-3.63 (m, 2H), 3.44 (q, J = 8.3 Hz, 1H), 3.19-2.84 (m, 4H),2.83-2.59 (m, 0H), 2.25-2.12 (m, 1H), 2.09 (s, 3H), 1.92 (dt, J = 13.8,7.1 Hz, 3H), 1.81 (d, J = 5.1 Hz, 1H), 1.76-1.63 (m, 4H), 1.52 (d, J =6.5 Hz, 8H). 187  663.4 1H NMR (400 MHz, DMSO-d6) delta 10.51 (s, 1H),9.92(s, 0.2 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.76 (s, 1H), 8.48-8.23 (m,2H), 7.79 (dd, J = 7.8, 1.5 Hz, 1H), 7.71-7.48 (m, 3H), 5.13 (p, J = 6.6Hz, 1H), 4.31 (q, J = 8.2 Hz, 1H), 3.88 (td, J = 14.8, 14.2, 7.2 Hz,1H), 3.72 (dd, J = 14.7, 8.2 Hz, 3H), 3.58 (t, J = 11.0 Hz, 1H), 3.36(d, J = 10.8 Hz, 1H), 3.14 (d, J = 11.0 Hz, 1H), 2.96 (d, J = 12.4 Hz,1H), 2.83-2.65 (m, 2H), 2.08 (s, 3H), 1.80 (h, J = 9.0 Hz, 2H), 1.70 (t,J = 5.9 Hz, 2H), 1.56-1.46 (m, 7H), 1.29 (s, 3H), 0.86 (t, J = 4.9 Hz,1H), 0.70-0.61 (m, 1H). 188  554.4 1H NMR (400 MHz, DMSO-d6) delta 10.59(s, 1H), 10.25 (s, 3.2 1H), 8.91 (d, J = 5.3 Hz, 1H), 8.77 (s, 1H), 8.39(dd, J = 6.6, 0.8 Hz, 1H), 8.33 (s, 1H), 7.80 (dd, J = 7.7, 1.5 Hz, 1H),7.71-7.62 (m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 5.18-5.07 (m, 1H), 4.43-4.30 (m, 1H), 3.69-3.56 (m, 1H), 3.51 (s, 2H), 3.05-2.90 (m, 4H),2.87-2.75 (m, 2H), 2.07-2.02 (m, 2H), 1.92-1.87 (m, 2H), 1.52 (d, J =6.6 Hz, 6H), 1.30 (s, 6H). 189  582.4 1H NMR (400 MHz, DMSO-d6) delta10.52 (s, 1H), 10.30 (s, 0.6 1H), 8.89 (d, J = 5.3 Hz, 1H), 8.76 (s,1H), 8.38 (dd, J = 6.5, 0.8 Hz, 1H), 8.32 (s, 1H), 7.79 (dd, J = 7.8,1.4 Hz, 1H), 7.69-7.61 (m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 5.18-5.06 (m,1H), 4.42- 4.29 (m, 1H), 3.74-3.58 (m, 2H), 3.37-3.30 (m, 1H), 3.03-2.90 (m, 2H), 2.84-2.78 (m, 4H), 1.94-1.85 (m, 1H), 1.82- 1.72 (m, 1H),1.52 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H), 1.18 (s, 3H), 1.11 (s, 3H). 190 582.3 1H NMR (400 MHz, DMSO-d6) delta 10.39 (s, 1H), 8.86-8.81 2.1 (m,1H), 8.78-8.70 (m, 1H), 8.39-8.24 (m, 2H), 7.83-7.74 (m, 1H), 7.69-7.53(m, 2H), 7.43 (dd, J = 12.9, 7.8 Hz, 1H), 5.17-5.05 (m, 1H), 4.56 (d, J= 6.8 Hz, 1H), 4.49 (s, 1H), 4.41- 4.19 (m, 4H), 4.19-3.98 (m, 3H),3.24-3.05 (m, 1H), 2.95- 2.78 (m, 2H), 2.65-2.54 (m, 1H), 2.14-2.04 (m,1H), 1.50 (dd, J = 6.6, 1.6 Hz, 6H), 1.29 (d, J = 5.8 Hz, 6H). 191 582.4 1H NMR (400 MHz, DMSO-d6) delta 10.29 (s, 1H), 9.42 (s, 0.9 1H),8.80 (s, 1H), 8.72 (s, 1H), 8.36-8.26 (m, 2H), 7.77 (dd, J = 7.8, 1.4Hz, 1H), 7.65-7.56 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 5.17-5.05 (m, 1H),4.33-4.24 (m, 1H), 3.37-3.32 (m, 2H), 2.99-2.82 (m, 4H), 2.73-2.66 (m,1H), 2.46-2.41 (m, 1H), 1.90-1.57 (m, 4H), 1.50 (dd, J = 6.7, 2.2 Hz,6H), 1.28 (s, 6H), 1.12-1.04 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H). 192 568.4 1H NMR (400 MHz, DMSO-d6) delta 10.56 (s, 1H), 10.36 (s, 1.1 1H),8.90 (d, J = 5.3 Hz, 1H), 8.76 (s, 1H), 8.38 (dd, J = 6.5, 0.8 Hz, 1H),8.33 (s, 1H), 7.79 (dd, J = 7.7, 1.5 Hz, 1H), 7.70-7.61 (m, 2H), 7.43(d, J = 7.8 Hz, 1H), 5.18-5.06 (m, 1H), 4.42- 4.31 (m, 1H), 3.69-3.62(m, 1H), 3.12 (d, J = 47.6 Hz, 2H), 2.99-2.89 (m, 2H), 2.86-2.74 (m,2H), 2.35-2.06 (m, 3H), 1.68-1.63 (m, 1H), 1.52 (d, J = 6.6 Hz, 6H),1.30 (s, 6H), 1.07 (dd, J = 11.0, 6.6 Hz, 3H). 193  677.4 1H NMR (400MHz, Chloroform-d) delta 11.37 (s, 1H), 8.52- 0.3 8.39 (m, 2H), 8.30 (d,J = 6.7 Hz, 1H), 8.09 (s, 1H), 8.02 (t, J = 7.6 Hz, 1H), 7.64-7.52 (m,2H), 7.30 (d, J = 7.8 Hz, 1H), 7.00 (s, 0H), 5.16 (p, J = 6.7 Hz, 1H),4.53-4.41 (m, 1H), 4.26 (d, J = 13.8 Hz, 2H), 4.00 (s, 2H), 3.82-3.52(m, 4H), 3.45-3.09 (m, 3H), 2.88 (d, J = 9.1 Hz, 2H), 2.74 (d, J = 11.9Hz, 1H), 2.21 (s, 0H), 2.09-1.97 (m, 2H), 1.92-1.58 (m, 17H), 1.25 (s,1H). 194  621.4 1H NMR (400 MHz, DMSO-d6) delta 9.46 (d, J = 8.3 Hz,1H), 9.6 8.77 (s, 1H), 8.45 (q, J = 4.6 Hz, 1H), 8.13 (s, 1H), 8.03 (s,1H), 7.77 (d, J = 7.7 Hz, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.45 (d, J =7.7 Hz, 1H), 5.25 (s, 1H), 4.37-4.24 (m, 1H), 3.58-3.47 (m, 1H), 3.39(d, J = 11.7 Hz, 2H), 3.03-2.92 (m, 2H), 2.91-2.78 (m, 3H), 2.76 (d, J =4.6 Hz, 3H), 2.24 (s, 3H), 1.84 (d, J = 14.2 Hz, 2H), 1.75-1.56 (m, 4H),1.54 (d, J = 6.6 Hz, 6H), 1.48- 1.35 (m, 1H), 1.31 (s, 6H). 195  679.41H NMR (400 MHz, DMSO-d6) delta 9.53 (d, J = 9.2 Hz, 1H), 6.0 8.95 (s,1H), 8.80 (d, J = 1.4 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.75 (d, J =7.8 Hz, 1H), 7.63-7.54 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 5.27 (s, 1H),4.54 (s, 1H), 4.42 (s, 1H), 4.40-4.27 (m, 1H), 3.57-3.46 (m, 1H), 3.40(d, J = 11.8 Hz, 2H), 3.04-2.92 (m, 2H), 2.92-2.73 (m, 4H), 2.24 (s,3H), 1.84 (d, J = 14.2 Hz, 2H), 1.76-1.58 (m, 3H), 1.54 (d, J = 6.5 Hz,6H), 1.48-1.34 (m, 1H), 1.31 (s, 6H), 0.93-0.88 (m, 2H), 0.88-0.77 (m,2H).

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated.

1. A method of treating a cancer associated with increased HPK1 activityin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein: one of R¹ and R²is H, —CN, —OH, halogen, or C₁₋₆ alkyl, and the other of R¹ and R² is H,halogen, or C₁₋₆ alkyl, wherein each C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH and halogen,or R¹ and R² together with the carbon to which they are attached form aC₃₋₇ monocyclic cycloalkyl or a 4-6 membered monocyclic heterocyclylhaving 1 or 2 heteroatoms independently selected from N, O, and S,wherein the C₃₋₇ monocyclic cycloalkyl and the 4-6 membered monocyclicheterocyclyl are each optionally substituted with one R¹¹ and are eachoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, or R¹ and R² together form═O; R¹¹ is i) 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy, ii) —S(O)₂C₁₋₆ alkyl, iii) —S(O)₂C₃₋₇ monocycliccycloalkyl, iv) C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl, or v) —C(O)R²¹; R²¹ is i) H, ii) C₃₋₇ monocyclicor bridged bicyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, and C₁₋₃ alkoxy, iii) 4-6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iv)5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independentlyselected from N, O, and S, wherein the 5-6 membered monocyclicheteroaryl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, v) —NH₂,vi) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionally substitutedwith 1-3 groups independently selected from —CN, —OH, halogen, and C₁₋₃alkoxy, vii) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the same ordifferent and wherein each C₁₋₆ alkyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy,viii) C₁₋₆ alkoxy optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl,or ix) C₁₋₆ alkyl optionally substituted with 1-3 groups independentlyselected from a) —CN, b) —OH, c) halogen, d) C₁₋₃ alkoxy, e) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, f) 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy, and g) —OC(O)C₁₋₆ alkyl optionally substituted with one—OH; R³ and R¹³ are each H, or R³ and R¹³ together form ═O; L¹ is acyclobutylene optionally substituted with 1-6 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; X is —NR¹⁵R¹⁶,wherein R¹⁵ and R¹⁶ are independently i) H, ii) C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iii) 4-7 memberedmonocyclic heterocyclyl having 1 or 2 heteroatoms independently selectedfrom N, O, and S, wherein the 4-7 membered monocyclic heterocyclyl isoptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, iv) —C(O)C₁₋₆ alkyl, whereinthe C₁₋₆ alkyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or v) C₁₋₆ alkyloptionally substituted with 1-6 groups independently selected from a)—CN, b) —OH, c) halogen, d) C₁₋₃ alkoxy, e) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, and f) 5-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; or X is a 4-10 membered monocyclic,fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl having 1-3heteroatoms independently selected from N, O, and S, wherein the 4-10membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl is optionally substituted with 1-5 R¹⁸; each R¹⁸ isindependently i) —CN, ii) a halogen, iii) —OH, iv) C₁₋₆ alkoxyoptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, v) C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —OH,halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, vi) —COOH, or vii)—C(O)N(R²²)₂, wherein each R²² is independently H or C₁₋₆ alkyl; X¹ is Nor CR¹⁷; R⁴, R⁵, R⁶, R¹⁰, and R¹⁷ are each independently H, halogen,C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁷ is i) H, ii) C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, or iii) C₃₋₇ monocycliccycloalkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy; Z is —O—, —C(R⁸)₂—, or—NR⁸—; each R⁸ is independently H or C₁₋₃ alkyl; A is a pyridinyl,pyridonyl, quinolinyl, or isoquinolinyl, each of which is optionallysubstituted with 1-4 R⁹; each R⁹ is independently i) halogen, ii) C₁₋₆alkoxy optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl, iii)—NH₂, iv) —NH(C₁₋₆ alkyl), wherein the C₁₋₆ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,and C₁₋₃ alkoxy, v) —N(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be thesame or different, and wherein each C₁₋₆ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, and C₁₋₃alkoxy, vi) —P(O)(C₁₋₆ alkyl)₂, wherein each C₁₋₆ alkyl can be the sameor different, and wherein each C₁₋₆ alkyl is optionally substituted with1-3 groups independently selected from —OH, halogen, and C₁₋₃ alkoxy,vii) —S(O)₂C₁₋₆ alkyl, viii) —S(O)₂N(R²³)₂, wherein each R²³ isindependently H or C₁₋₆ alkyl, ix) C₁₋₆ alkyl optionally substitutedwith 1-3 groups independently selected from a) —OH, b) halogen, c) C₁₋₃alkoxy, d) C₃₋₇ monocyclic cycloalkyl, e) 5-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 5-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from oxo and C₁₋₃alkyl, and f) —NR²⁰C(O)OC₁₋₃ alkyl, wherein R²⁰ is H or C₁₋₃ alkyl, x)C₃₋₇ monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,xi) 5-6 membered monocyclic heteroaryl having 1-4 heteroatomsindependently selected from N, O, and S, wherein the 5-6 memberedmonocyclic heteroaryl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,xii) 4-6 membered monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy, xiii) —COOH, xiv) —C(O)N(R¹⁹)₂, or xv) —C₁₋₃ alkylC(O)N(R¹⁹)₂;and each R¹⁹ is independently i) H, ii) —S(O)₂C₁₋₆ alkyl, iii) C₁₋₆alkyl optionally substituted with 1-6 groups independently selected from—CN, —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl, iv) C₃₋₇monocyclic cycloalkyl optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, C₁₋₆ alkyl, and C₁₋₆alkoxy, wherein the C₁₋₆ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy, or v)4-6 membered monocyclic heterocyclyl having 1-3 heteroatomsindependently selected from N, O, and S, wherein the 4-6 memberedmonocyclic heterocyclyl is optionally substituted with 1-6 groupsindependently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy.
 2. The method of claim 1, wherein the compound is of Formula II,

or a pharmaceutically acceptable salt thereof, wherein each R¹² isindependently —OH, halogen, C₁₋₃ alkyl, or C₁₋₃ alkoxy; and n is 0, 1,2, 3, or
 4. 3. The method of claim 2, wherein the compound is of FormulaIIa,

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,or a pharmaceutically acceptable salt thereof, wherein R³ and R¹³together form ═O.
 5. The method of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X¹ is CH.
 6. (canceled)
 7. The claim 1,or a pharmaceutically acceptable salt thereof, wherein Z is NH. 8.(canceled)
 9. The method of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R⁴, R⁵, R⁶, and R¹⁰ are H.
 10. The method of claim2, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or2.
 11. The method of claim 1, wherein the compound is of Formula III,

or a pharmaceutically acceptable salt thereof, wherein: one of R¹ and R²is —OH or C₁₋₃ alkyl, and the other of R¹ and R² is C₁₋₃ alkyl, or R¹and R² together with the carbon to which they are attached form a 4-6membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4-6 membered monocyclicheterocyclyl is optionally substituted with one R¹¹ and optionallysubstituted with 1-3 groups independently selected from —OH, halogen,oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy; R¹¹ is i) 4-6 membered monocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N, O,and S, wherein the 4-6 membered monocyclic heterocyclyl is optionallysubstituted with 1-3 groups independently selected from —CN, —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy, or ii) —C(O)R²¹; R²¹ is i)C₃₋₇ monocyclic or bridged bicyclic cycloalkyl optionally substitutedwith 1-3 groups independently selected from —CN, —OH, halogen, C₁₋₃alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, and C₁₋₃alkoxy, ii) 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy, iii) 5-6 membered monocyclic heteroaryl having 1-4heteroatoms independently selected from N, O, and S, wherein the 5-6membered monocyclic heteroaryl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃alkoxy, or iv) C₁₋₆ alkoxy optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₃₋₇monocyclic cycloalkyl, v) C₁₋₆ alkyl optionally substituted with 1-3groups independently selected from a) —CN, b) —OH, c) halogen, d) C₁₋₃alkoxy, and e) 4-6 membered monocyclic heterocyclyl having 1 or 2heteroatoms independently selected from N, O, and S, wherein the 4-6membered monocyclic heterocyclyl is optionally substituted with 1-3groups independently selected from —CN, —OH, halogen, oxo, C₁₋₃ alkyl,and C₁₋₃ alkoxy; X is —NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ are independently i)H, or ii) C₁₋₆ alkyl optionally substituted with 1-6 groupsindependently selected from a) —OH, b) halogen, and c) C₁₋₃ alkoxy; or Xis a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic, orspirocyclic heterocyclyl having 1-3 heteroatoms independently selectedfrom N, O, and S, wherein the 4-10 membered monocyclic, fused bicyclic,bridged bicyclic, or spirocyclic heterocyclyl is optionally substitutedwith 1-5 R¹⁸; each R¹⁸ is independently i) a halogen, ii) —OH, or iii)C₁₋₆ alkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; R⁷ isC₁₋₆ alkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇ monocyclic cycloalkyl; A is apyridinyl, pyridonyl, or isoquinolinyl, each of which is optionallysubstituted with 1-4 R⁹; each R⁹ is independently i) a halogen, ii) C₁₋₆alkoxy optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, C₁₋₃ alkyl, and C₃₋₇ monocyclic cycloalkyl, iii)—NH₂, iv) —NH(C₁₋₃ alkyl), wherein the C₁₋₃ alkyl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,and C₁₋₃ alkoxy, v) —N(C₁₋₃ alkyl)₂, wherein each C₁₋₃ alkyl can be thesame or different, and wherein each C₁₋₃ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH, halogen, and C₁₋₃alkoxy, vi) C₁₋₆ alkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkoxy, and C₃₋₇monocyclic cycloalkyl, or vii) —C(O)N(R¹⁹)₂; and each R¹⁹ isindependently i) H, ii) C₁₋₆ alkyl optionally substituted with 1-6groups independently selected from —CN, —OH, halogen, C₁₋₃ alkoxy, andC₃₋₇ monocyclic cycloalkyl, or iii) C₃₋₇ monocyclic cycloalkyloptionally substituted with 1-6 groups independently selected from —CN,—OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl isoptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, and C₁₋₃ alkoxy.
 12. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ and R² togetherwith the carbon to which they are attached form a piperidinyl optionallysubstituted with one R¹¹ and optionally substituted with 1-3 groupsindependently selected from —OH, halogen, oxo, C₁₋₃ alkyl, and C₁₋₃alkoxy.
 13. The method of claim 1, wherein the compound is of FormulaIV,

or a pharmaceutically acceptable salt thereof.
 14. The method of claim13, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is a 4membered monocyclic heterocyclyl having 1 or 2 heteroatoms independentlyselected from N, O, and S, wherein the 4 membered monocyclicheterocyclyl is optionally substituted with 1-3 groups independentlyselected from —CN, —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy. 15.(canceled)
 16. The method of claim 13, or a pharmaceutically acceptablesalt thereof, wherein R¹¹ is —C(O)R²¹.
 17. The method of claim 16, or apharmaceutically acceptable salt thereof, wherein R²¹ is C₁₋₆ alkyloptionally substituted with 1-3 groups independently selected from —CN,—OH, halogen, oxetanyl, C₁₋₃ alkoxy, and —OC(O)CH(CH₃)OH.
 18. (canceled)19. The method of claim 16, or a pharmaceutically acceptable saltthereof, wherein R²¹ is cyclopropyl, cyclobutyl, cyclopentyl, or C₅bridged bicyclic cycloalkyl, each of which is optionally substitutedwith 1-3 groups independently selected from —CN, —OH, halogen, C₁₋₃alkyl, and C₁₋₃ alkoxy, wherein the C₁₋₃ alkyl is optionally substitutedwith 1-3 groups independently selected from —OH and halogen.
 20. Themethod of claim 16, or a pharmaceutically acceptable salt thereof,wherein R²¹ is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, eachof which is optionally substituted with 1-3 groups independentlyselected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.
 21. The methodof claim 16, or a pharmaceutically acceptable salt thereof, wherein R²¹is a 5-membered heteroaryl having 1-4 heteroatoms independently selectedfrom N, O, and S, wherein the 5-membered heteroaryl is optionallysubstituted with 1-3 groups independently selected from —OH, halogen,methyl, and —OCH₃.
 22. The method of claim 16, or a pharmaceuticallyacceptable salt thereof, wherein R²¹ is oxazolyl, thiazolyl, isoxazolyl,oxadiazolyl, or triazolyl, each of which is optionally substituted with1-3 groups independently selected from —OH, halogen, C₁₋₃ alkyl, andC₁₋₃ alkoxy. 23-26. (canceled)
 27. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ and R² togetherwith the carbon to which they are attached form a tetrahydropyranyloptionally substituted with 1-3 groups independently selected from —OH,halogen, oxo, C₁₋₃ alkyl, and C₁₋₃ alkoxy.
 28. The method of claim 1,wherein the compound is of Formula V,

or a pharmaceutically acceptable salt thereof.
 29. The method of claim1, or a pharmaceutically acceptable salt thereof, wherein one of R¹ andR² is —OH, methyl, or ethyl and the other of R¹ and R² is methyl orethyl.
 30. (canceled)
 31. (canceled)
 32. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein A is pyridinyloptionally substituted with 1-4 R⁹ or A is pyridonyl optionallysubstituted with 1-3 R⁹. 33-37. (canceled)
 38. The method of claim 32,or a pharmaceutically acceptable salt thereof, wherein each R⁹ isindependently: i) halogen, ii) —NH₂, iii) —NH(C₁₋₃ alkyl), iv) —N(C₁₋₃alkyl)₂, wherein each C₁₋₃ alkyl is the same or different, v) C₁₋₃ alkyloptionally substituted with 1-3 groups independently selected from —OHand halogen, vi) —OCH₃ optionally substituted with 1-3 halogen groups,or vii) —C(O)N(R¹⁹)₂. 39-43. (canceled)
 44. The method of claim 38, or apharmaceutically acceptable salt thereof, wherein one or both R¹⁹ isC₁₋₄ alkyl optionally substituted with 1-3 groups independently selectedfrom —OH, halogen, and C₁₋₃ alkoxy.
 45. The method of claim 38, or apharmaceutically acceptable salt thereof, wherein one or both R¹⁹ isC₃₋₅ monocyclic cycloalkyl optionally substituted with 1-3 groupsindependently selected from —OH, halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy,wherein the C₁₋₃ alkyl is optionally substituted with 1-3 groupsindependently selected from —CN, —OH, halogen, and C₁₋₃ alkoxy.
 46. Thecompound of method of claim 38, or a pharmaceutically acceptable saltthereof, wherein each R¹⁹ is independently: i) H, ii) methyl, iii) ethyloptionally substituted with 1 or 2 groups independently selected from—OH, fluoro, and —OCH₃, iv) n-propyl optionally substituted with 1 or 2groups independently selected from fluoro and —OCH₃, v) isopropyloptionally substituted with 1 or 2 fluoro groups, vi) n-butyl, vii)isobutyl optionally substituted with 1 or 2 fluoro groups, viii)sec-butyl, ix) tert-butyl, x) cyclopropyl optionally substituted withone methyl group, wherein the methyl is optionally substituted with 1-3groups independently selected from fluoro and —OCH₃, or xi) cyclobutyl.47-49. (canceled)
 50. The method of claim 38, or a pharmaceuticallyacceptable salt thereof, wherein A is substituted with 1-3 R⁹, andwherein each R⁹ is independently fluoro, chloro, methyl, —OCH₃, —CH₂OH,—N(CH₃)₂, —C(O)NH₂, —C(O)NH(CH₃), —C(O)NH(isopropyl),


51. (canceled)
 52. The method of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁷ is methyl, ethyl, isopropyl, orsec-butyl.
 53. (canceled)
 54. (canceled)
 55. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein X is NR¹⁵R¹⁶.
 56. Themethod of claim 55, or a pharmaceutically acceptable salt thereof,wherein one or both of R¹⁵ and R¹⁶ are a C₁₋₆ alkyl optionallysubstituted with 1-3 groups independently selected from —OH, halogen,and —OCH₃. 57-62. (canceled)
 63. The method of claim 1, or apharmaceutically acceptable salt thereof, wherein X is a 4-9 memberedmonocyclic, fused bicyclic, bridged bicyclic, or spirocyclicheterocyclyl having 1 or 2 heteroatoms independently selected from N andO, wherein the 4-9 membered monocyclic, fused bicyclic, bridgedbicyclic, or spirocyclic heterocyclyl is optionally substituted with 1-5R¹⁸.
 64. (canceled)
 65. The method of claim 63, or a pharmaceuticallyacceptable salt thereof, wherein X is azetidinyl, pyrrolidinyl,piperidinyl, or morpholinyl, each of which is optionally substitutedwith 1-5 R¹⁸. 66-68. (canceled)
 69. The method of claim 63, or apharmaceutically acceptable salt thereof, wherein X is:

each of which is optionally substituted with 1-5 R¹⁸.
 70. (canceled) 71.The method of claim 69, or a pharmaceutically acceptable salt thereof,wherein X is:

each of which is optionally substituted with 1-4 R¹⁸.
 72. (canceled) 73.(canceled)
 74. The method of claim 63, or a pharmaceutically acceptablesalt thereof, wherein each R¹⁸ is independently i) —OH, ii) fluoro, oriii) C₁₋₃ alkyl optionally substituted with 1-3 groups independentlyselected from —OH and halogen. 75-77. (canceled)
 78. The method of claim71, or a pharmaceutically acceptable salt thereof, wherein X is

79-138. (canceled)